Antagonists of T2R54 and compositions and uses thereof

ABSTRACT

The present disclosure generally provides compounds that antagonize certain T2R taste receptors, including related uses, methods, and compositions for the reduction of bitter taste and/or the enhancement of sweet taste. In certain aspects, the disclosure provides flavored articles or flavored compositions comprising such compounds, as well as uses of such compounds to reduce the bitter taste and/or enhance the sweet taste of such flavored articles or flavored compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is the United States national stage applicationof PCT Application No. PCT/US2019/045684, filed Aug. 8, 2019, whichclaims the benefit of priority of U.S. Provisional Application No.62/717,121, filed Aug. 10, 2018, which is hereby incorporated byreference as though set forth herein in its entirety.

TECHNICAL FIELD

The present disclosure generally provides compounds that antagonizecertain T2R taste receptors, including related uses, methods, andcompositions for the reduction of bitter taste and/or the enhancement ofsweet taste. In certain aspects, the disclosure provides flavoredarticles or flavored compositions comprising such compounds, as well asuses of such compounds to reduce the bitter taste and/or enhance thesweet taste of such flavored articles or flavored compositions.

DESCRIPTION OF RELATED ART

The taste system provides sensory information about the chemicalcomposition of the external world. Taste transduction is one of the mostsophisticated forms of chemical-triggered sensation in animals.Signaling of taste is found throughout the animal kingdom, from simplemetazoans to the most complex of vertebrates. Mammals are believed tohave five basic taste modalities: sweet, bitter, sour, salty, and umami.

Obesity, diabetes, and cardiovascular disease are major health concernsthroughout the world, and are growing at an alarming rate. Sugar andcalories are key components that can be limited to render a positivenutritional effect on health. Even so, because a number of foods containcomponents that agonize bitter taste receptors, consumers often usesugar and other sweeteners to offset the perception of bitter taste insuch foods. Further, certain nutritionally useful foods, such asvegetable proteins, agonize bitter taste receptors. Thus, despite theirnutritional value, consumers may avoid such foods because of theirperceived poor taste. Further, many medicinal compounds, such asantibiotics, have a distinctly bitter taste. Therefore, pharmaceuticalmanufacturers must employ complicated formulation technologies to permitsubjects to take such medicines orally without experiencing displeasure.

But the physiological basis concerning the perception of bitter taste isstill not well understood. Many bitter compounds produce their bittertaste, at least in part, by modulating certain cell surface receptors,some of which belong to a family of seven transmembrane domain receptorsthat interact with intracellular G proteins. These include a family ofG-coupled protein receptors (GCPRs), termed T2Rs, which are found inhumans and rodents. Humans express at least several dozen differentreceptors that fall within the T2R family. One of these receptors foundin humans is termed hT2R54. This receptor is believed to play a key rolein the human perception of bitter taste.

Some compounds are known to antagonize hT2R54. Even so, such compoundsmay only antagonize the hT2R54 receptor weakly, or may interact withother taste receptors modify the taste of a flavored article in waysthat humans do not perceive as offering an improvement in taste.Therefore, there is a continuing need to discover compounds thatantagonize hT2R54, with the goal of discovering compounds that reducethe human perception of bitter taste without otherwise modifying thetaste of an article in ways that humans tend to dislike.

SUMMARY

The present disclosure provides compounds that were discovered asantagonists, such as selective antagonists, of hT2R54. These compoundsprovide a broader array of compounds that can be used in food productsor drug products to reduce the perception of bitter taste, and, in somecases, even have a concomitant enhancement of the perception of sweettaste in such products.

In a first aspect, the disclosure provides compounds of formula (I):

or a salt thereof, wherein:

-   -   X¹ and X² are each independently an oxygen atom or        >C(R^(2A))(R^(2B));    -   X³ is a direct bond or >C(R^(2C))(R^(2D));    -   X⁴ is >C(R^(2E))(R^(2F));    -   R^(A) is a halogen atom, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl,        C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, or (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R¹ is a halogen atom, —C(O)—R^(1A), —C(O)—O—R^(1A), —O—R^(1A),        —O—C(O)—R^(1A), or C₁₋₆alkyl, where the alkyl group is        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Y);    -   R^(1A) is a hydrogen atom or C₁₋₆alkyl, wherein the alkyl group        is optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Y);    -   R^(1Y) is a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl,        C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, C₂₋₆haloalkenyloxy, and        (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R^(1Z) is a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl,        C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, C₂₋₆haloalkenyloxy,        (C₁₋₆alkoxy)-C₁₋₆alkyl, C₁₋₆alkyl, and C₂₋₆alkenyl;    -   R² is —N(R⁵)(R⁶), wherein R⁵ and R⁶ optionally combine with the        nitrogen atom to which they are attached to form a        nitrogen-containing C₂₋₆ heterocyclic ring, which is optionally        substituted by C₁₋₄alkyl; or    -   R² is or

-   -   R² is a hydrogen atom, a halogen atom, C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the        carbocyclyl, heterocyclyl, aryl, and heteroaryl are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   X⁵ is >NR^(2G);    -   X⁶ is C₁₋₆alkylene, which is optionally substituted one or more        times by substituents selected independently from the group        consisting of R^(1Y); or    -   X⁷ is an oxygen atom, a sulfur atom, >N—R^(2L), or        >C(R^(2J))(R^(2K));    -   X⁸, X⁹, X¹⁹, and X¹¹ are each independently a direct bond, an        oxygen atom, a sulfur atom, or >C(R^(2M))(R^(2N)), wherein no        more than one of X⁸, X⁹, X¹⁹, and X¹¹ is a direct bond, and        wherein no more than one of X⁸, X⁹, X¹⁹, and X¹¹ is an oxygen        atom or a sulfur atom;    -   X¹² is an oxygen atom, a sulfur atom, or >N—R^(2L);    -   X¹³ is a direct bond or >NR^(2E);    -   R^(2A), R^(2B), R^(2C), R^(2D), R^(2E), R^(2F), R^(2K), R^(2M),        and R^(2N) are each independently a hydrogen atom, a halogen        atom, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH,        —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl),        —NH—C(O)—(C₁₋₆alkyl), —NH—C(O)—O—(C₁₋₆alkyl),        —C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂,        —S(O)₂—(C₁₋₆alkyl), —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, (C₁₋₆alkoxy)-C₁₋₆alkyl; or R^(2A) and        R^(2B), or R^(2C) and R^(2D), or R^(2E) and R^(2F), or R^(2M)        and R^(2N) optionally combine to form an oxo group; or any two        of R^(2M) and R^(2N) attached to adjacent carbon atoms        optionally combine to form a fused ring selected from the group        consisting of phenyl, C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, and C₂₋₅        heterocyclyl, wherein each of the fused rings is optionally        substituted one or more times by substituents selected        independently from R^(1Z);    -   R^(2G) and R^(2E) are each independently a hydrogen atom,        C₁₋₆alkyl, C₁₋₆haloalkyl, or (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R^(2J) is —R⁴ or —X¹⁴—R⁴;    -   R^(2L) is —C(O)—R³, —C(O)—X¹⁴—R⁴, —C(S)—R³, —C(S)—X¹⁴—R⁴,        —S(O)₂—R³, —S(O)₂—X¹⁴—R⁴, or —X¹⁴—R⁴;    -   X¹⁴ is C₁₋₈alkylene, which is optionally substituted by one or        more times by substituents selected independently from the group        consisting of R^(1Y);    -   R³ is a hydrogen atom, —OH, —NH₂, —O—R^(3B), —NH—R^(3B),        —N(R^(3B))(R^(3C)), —O—C(O)—R^(3B), —NH—C(O)—R^(3B),        —N(R^(3C))—C(O)—R^(3B), C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the carbocyclyl,        heterocyclyl, aryl, and heteroaryl are each optionally        substituted one or more times by substituents selected        independently from R^(3A), wherein any two R^(3A) attached to        adjacent carbon atoms optionally combine to form a fused ring        selected from the group consisting of phenyl, C₂₋₅ heteroaryl,        C₄₋₈cycloalkyl, and C₂₋₅ heterocyclyl, wherein each of the fused        rings is optionally substituted one or more times by        substituents selected independently from R^(1Z), and wherein,        when R^(3B) and R^(3C) are attached to the same nitrogen atom,        R^(3B) and R^(3C) optionally combine with the nitrogen atom to        which they are attached to form a nitrogen-containing C₂₋₆        heterocyclic ring, which is optionally substituted by C₁₋₄alkyl;    -   R^(3A) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—R^(3D), —NH—R^(3D),        —N(R^(3D))(R^(3E)), —C(O)—R^(3D), —O—C(O)—R^(3D),        —NH—C(O)—R^(3D), —C(O)—O—R^(3D), —C(O)—NH—R^(3D),        —C(O)—N(R^(3D))(R^(3E)), —S(O)₂—R^(3D), —O—S(O)₂—R^(3D),        —NH—S(O)₂—R^(3D), —S(O)₂—O—R^(3D), —S(O)₂—NH—R^(3D),        —S(O)₂—N(R^(3D))(R^(3E)), C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀        carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄        heteroaryl, wherein the alkyl and alkenyl are each optionally        substituted one or more times by substituents selected        independently from the group consisting of R^(3Y), and wherein        the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(3Z);    -   R^(3B), R^(3C), R^(3D), and R^(3E) are each independently        C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl        are each optionally substituted one or more times by        substituents selected independently from the group consisting of        R^(3Y), and wherein the carbocyclyl, heterocyclyl, aryl, and        heteroaryl are each optionally substituted one or more times by        substituents selected independently from the group consisting of        R^(3Z); R^(3Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂,        —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂,        —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,        —C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R^(3Z) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, (C₁₋₆alkoxy)-C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein        the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are        each optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R⁴ is a hydrogen atom, a halogen atom, —CN, nitro, oxo, —OH,        —NH₂, —O—R^(4B), —NH—R^(4B), —N(R^(4B))(R^(4C)), C(O)—R^(4B),        —O—C(O)—R^(4B), —NH—C(O)—R^(4B), —N(R^(4C))—C(O)—R^(4B),        —C(O)—O—R^(4B), —C(O)—NH—R^(4B)—C(O)N(R^(4B))(R^(4C)),        —S(O)₂—R^(4D), —O—S(O)₂—R^(4D), —NH—S(O)₂—R^(4D),        —S(O)₂—O—R^(4D), —S(O)₂—NH—R^(4D), —S(O)₂—N(R^(4D))(R^(4E)),        C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄        heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, and        heteroaryl are each optionally substituted one or more times by        substituents selected independently from R^(4A), wherein any two        R^(4A) attached to adjacent carbon atoms optionally combine to        form a fused ring selected from the group consisting of phenyl,        C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, and C₂₋₅ heterocyclyl, wherein        each of the fused rings is optionally substituted one or more        times by substituents selected independently from R^(1Z), and        wherein, when R^(4B) and R^(4C) are attached to the same        nitrogen atom, R^(4B) and R^(4C) optionally combine with the        nitrogen atom to which they are attached to form a        nitrogen-containing C₂₋₆ heterocyclic ring, which is optionally        substituted by C₁₋₄alkyl;    -   R^(4A) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH. —NH—C(O)H, —C(O)—NH₂, —O—R^(4D), —NH—R^(4D),        —N(R^(4D))(R^(4E)), —C(O)—R^(4D), —O—C(O)—R^(4D),        —NH—C(O)—R^(4D), —N(R^(4E))—C(O)—R^(4D), —C(O)—O—R^(4D),        —C(O)—NH—R^(4D), —C(O)—N(R^(4D))(R^(4E)), C₁₋₈alkyl,        C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl,        and C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(4Y), and        wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are        each optionally substituted one or more times by substituents        selected independently from R^(4Z);    -   R^(4B), R^(4C), R^(4D), and R^(4E) are each independently        C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl        are each optionally substituted one or more times by        substituents selected independently from R^(4Y), and wherein the        carbocyclyl, heterocyclyl, aryl, and heteroaryl are each        optionally substituted one or more times by substituents        selected independently from R^(4Z);    -   R^(4Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R^(4Z) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        (C₁₋₆alkoxy)-C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, and        C₂₋₆haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl,        and heteroaryl groups are each optionally substituted one or        more times by substituents selected independently from the group        consisting of R^(1Z);    -   R⁵ is —C(O)—R³, —C(O)—X¹⁴—R⁴, —C(S)—R³, —C(S)—X¹⁴—R⁴, —S(O)₂—R³,        —S(O)₂—X¹⁴—R⁴, or —X¹⁴—R⁴;    -   R⁶ is a hydrogen atom or C₁₋₈alkyl, wherein the alkyl is        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(6Y);    -   R^(6Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R⁷ is a hydrogen atom, a halogen atom, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₁₋₆alkoxy, C₁₋₆haloalkoxy, or (C₁₋₆alkyl)-O—C₁₋₆alkyl; and    -   n is 0, 1, or 2.

In a second aspect, the disclosure provides uses of compounds of thefirst aspect (including any embodiments thereof).

In a third aspect, the disclosure provides uses of compounds of thefirst aspect (including any embodiments thereof) to reduce thebitterness and/or enhance the sweetness of a comestible composition or apharmaceutical composition. In some embodiments, the disclosure providesuses of compounds of the first aspect (including any embodimentsthereof) to reduce the bitterness of a comestible composition. In somefurther such embodiments, the comestible composition is a flavoredarticle, such as a flavored food product. In some other embodiments, thedisclosure provides uses of compounds of the first aspect (including anyembodiments thereof) to reduce the bitterness of a pharmaceuticalcomposition, such as a pharmaceutical composition (tablet, capsule,elixir, etc.) for oral administration.

In a fourth aspect, the disclosure provides uses of compounds of thefirst aspect (including any embodiments thereof) in the manufacture of aproduct for the reduction of bitter taste and/or the enhancement ofsweet taste in the product. In some embodiments, the disclosure providesuses of compounds of the first aspect (including any embodimentsthereof) in the manufacture of a flavored article, such as a flavoredfood or beverage product, for the reduction of bitter taste in theproduct. In some other embodiments, the disclosure provides uses ofcompounds of the first aspect (including any embodiments thereof) in themanufacture of a medicament for the reduction of bitter taste in themedicament.

In a fifth aspect, the disclosure provides uses of compounds of thefirst aspect (including any embodiments thereof) to antagonize one ormore human T2R taste receptors, such as one or more human T2R54 tastereceptors.

In a sixth aspect, the disclosure provides methods of reducing a bittertaste and/or enhancing a sweet taste of a flavored composition or apharmaceutical composition, the method comprising introducing an amount(such as an effective amount) of one or more compounds of the firstaspect (including any embodiments thereof) to the flavored compositionor the pharmaceutical composition. In some embodiments, the disclosureprovides methods of reducing a bitter taste of a flavored composition,the method comprising introducing an amount (such as an effectiveamount) of one or more compounds of the first aspect (including anyembodiments thereof) to the flavored composition. In some suchembodiments, the flavored composition if a food or beverage product. Insome other embodiments, the disclosure provides methods of reducing abitter taste of a pharmaceutical composition, the method comprisingintroducing an amount (such as an effective amount) of one or morecompounds of the first aspect (including any embodiments thereof) to thepharmaceutical composition.

In a seventh aspect, the disclosure provides methods of antagonizing ahuman T2R receptor, the methods comprising contacting a human T2Rreceptor with one or more compounds of the first aspect (including anyembodiments thereof). In some embodiments thereof, the method comprisescontacting a humanT2R54 receptor with one or more compounds of the firstaspect (including any embodiments thereof). In some embodiments, thecontacting comprises orally ingesting a composition comprising one ormore compounds of the first aspect (including any embodiments thereof).In some such embodiments, composition is a flavored composition, such asa food or beverage product. In some other such embodiments, thecomposition is a pharmaceutical composition.

In an eighth aspect, the disclosure provides a composition comprising anamount of one or more compounds of the first aspect (including anyembodiments thereof). In some embodiments, the composition comprises oneor more bitter compounds and a bitter-reducing effective amount of oneor more compounds of the first aspect (including any embodimentsthereof). In some further embodiments, the composition is apharmaceutical composition and the bitter compounds are one or morepharmaceutical compounds, such as active pharmaceutical ingredients(APIs). In some other embodiments, the composition is a flavoredcomposition, such as a food or beverage product, and the bittercompounds are artificial sweeteners, caffeine, proteins (such as plantproteins), amino acids, compounds derived from natural plant extracts,and the like.

Further aspects, and embodiments thereof, are set forth below in theDetailed Description, the Drawings, the Abstract, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are provided for purposes of illustrating variousembodiments of the compositions and methods disclosed herein. Thedrawings are provided for illustrative purposes only, and are notintended to describe any preferred compositions or preferred methods, orto serve as a source of any limitations on the scope of the claimedinventions.

FIG. 1 shows a graph of a dose-response of acetaminophen on anhT2R54-expressing cell line and the host cell line (not expressing thebitter taste receptor).

FIG. 2 shows a graph of the effect of an increase in a test compoundconcentration on acetaminophen dose-response (DR) on hT2R54-expressingcells. The test compound dose dependency shifts the DR curve to theright, but also causes a decrease in efficacy of acetaminophen,suggesting the test compound behaves as a non-competitive antagonist ofhT2R54. Each increase in dosage shifted the curve rightward anddownward; in order from left to right, the DR curves respectivelycorrespond to 0, 50 μM, 200 μM, 400 μM, and 800 μM of test compound.

DETAILED DESCRIPTION

The following Detailed Description sets forth various aspects andembodiments provided herein. The description is to be read from theperspective of the person of ordinary skill in the relevant art.Therefore, information that is well known to such ordinarily skilledartisans is not necessarily included.

Definitions

The following terms and phrases have the meanings indicated below,unless otherwise provided herein. This disclosure may employ other termsand phrases not expressly defined herein. Such other terms and phraseshave the meanings that they would possess within the context of thisdisclosure to those of ordinary skill in the art. In some instances, aterm or phrase may be defined in the singular or plural. In suchinstances, it is understood that any term in the singular may includeits plural counterpart and vice versa, unless expressly indicated to thecontrary

As used herein, “solvate” means a compound formed by the interaction ofone or more solvent molecules and one or more compounds describedherein. In some embodiments, the solvates are physiologically acceptablesolvates, such as hydrates.

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers, refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄alkyl” or “C₁₋₄alkyl” group refers to allalkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

As used herein, “halogen” or “halo” means any one of the radio-stableatoms of column 7 of the Periodic Table of the Elements, such asfluorine, chlorine, bromine, or iodine. In some embodiments, “halogen”or “halo” refer to fluorine or chlorine.

As used herein, “alkyl” means a straight or branched hydrocarbon chainthat is fully saturated (i.e., contains no double or triple bonds). Insome embodiments, an alkyl group has 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group may bedesignated as “C₁₋₄alkyl” or similar designations. By way of exampleonly, “C₁₋₄alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, and the like. Unless indicated to the contrary,the term “alkyl” refers to a group that is not further substituted.

As used herein, “substituted alkyl” means an alkyl group substitutedwith one or more substituents independently selected from C₁-C₆alkenyl,C₁-C₆alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl (optionallysubstituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), 3-10 membered heterocyclyl (optionally substitutedwith halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), aryl (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), halo, cyano, hydroxy, C₁-C₆alkoxy,aryloxy (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), C₃-C₇ carbocyclyloxy (optionallysubstituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), 3-10 membered heterocyclyl-oxy (optionally substitutedwith halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substitutedwith halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), C₃-C₇-carbocyclyl-C₁-C₆-alkoxy (optionally substitutedwith halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), 3-10 membered heterocyclyl-C₁-C₆-alkoxy (optionallysubstituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), aryl(C₁-C₆)alkoxy (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10membered heteroaryl(C₁-C₆)alkoxy (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF3), halo(C₁-C₆)alkoxy(e.g., —OCF₃), C₁-C₆alkylthio, arylthio (optionally substituted withhalo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),C₃-C₇ carbocyclylthio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10 memberedheterocyclyl-thio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl-thio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10membered heterocyclyl-C₁-C₆-alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),aryl(C₁-C₆)alkylthio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), amino,nitro, 0-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O).

As used herein, “alkoxy” means a moiety of the formula —OR wherein R isan alkyl, as is defined above, such as “C₁₋₉alkoxy”, including but notlimited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy),n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” means a moiety of the formula —SR wherein Ris an alkyl as is defined above, such as “C₁₋₉alkylthio” and the like,including but not limited to methylmercapto, ethylmercapto,n-propylmercapto, 1-methylethylmercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like.

As used herein, “alkenyl” means a straight or branched hydrocarbon chaincontaining one or more double bonds. In some embodiments, the alkenylgroup has from 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term “alkenyl” where no numericalrange is designated. The alkenyl group may also be a medium size alkenylhaving 2 to 9 carbon atoms. The alkenyl group could also be a loweralkenyl having 2 to 4 carbon atoms. The alkenyl group may be designatedas “C₂₋₄ alkenyl” or similar designations. By way of example only,“C₂₋₄alkenyl” indicates that there are two to four carbon atoms in thealkenyl chain, i.e., the alkenyl chain is selected from the groupconsisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl,buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl,2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl,buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typicalalkenyl groups include, but are in no way limited to, ethenyl, propenyl,butenyl, pentenyl, and hexenyl, and the like. Unless indicated to thecontrary, the term “alkenyl” refers to a group that is not furthersubstituted.

As used herein, “alkynyl” means a straight or branched hydrocarbon chaincontaining one or more triple bonds. In some embodiments, the alkynylgroup has from 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term “alkynyl” where no numericalrange is designated. The alkynyl group may also be a medium size alkynylhaving 2 to 9 carbon atoms. The alkynyl group could also be a loweralkynyl having 2 to 4 carbon atoms. The alkynyl group may be designatedas “C₂₋₄ alkynyl” or similar designations. By way of example only,“C₂₋₄alkynyl” indicates that there are two to four carbon atoms in thealkynyl chain, i.e., the alkynyl chain is selected from the groupconsisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl,butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in noway limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, andthe like. Unless indicated to the contrary, the term “alkynyl” refers toa group that is not further substituted.

As used herein, “heteroalkyl” means a straight or branched hydrocarbonchain containing one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen, and sulfur, inthe chain backbone. In some embodiments, the heteroalkyl group has from1 to 20 carbon atom, although the present definition also covers theoccurrence of the term “heteroalkyl” where no numerical range isdesignated. The heteroalkyl group may also be a medium size heteroalkylhaving 1 to 9 carbon atoms. The heteroalkyl group could also be a lowerheteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may bedesignated as “C₁₋₄ heteroalkyl” or similar designations. Theheteroalkyl group may contain one or more heteroatoms. By way of exampleonly, “C₁₋₄ heteroalkyl” indicates that there are one to four carbonatoms in the heteroalkyl chain and additionally one or more heteroatomsin the backbone of the chain. Unless indicated to the contrary, the term“heteroalkyl” refers to a group that is not further substituted.

As used herein, “alkylene” means a branched or straight chain fullysaturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). In some embodiments, the alkylenegroup has from 1 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term alkylene where no numerical rangeis designated. The alkylene group may also be a medium size alkylenehaving 1 to 9 carbon atoms. The alkylene group could also be a loweralkylene having 1 to 4 carbon atoms. The alkylene group may bedesignated as “C₁₋₄alkylene” or similar designations. By way of exampleonly, “C₁₋₄alkylene” indicates that there are one to four carbon atomsin the alkylene chain, i.e., the alkylene chain is selected from thegroup consisting of methylene, ethylene, ethan-1,1-diyl, propylene,propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene,butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl,1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene,1,2-dimethyl-ethylene, and 1-ethyl-ethylene. Unless indicated to thecontrary, the term “alkylene” refers to a group that is not furthersubstituted.

As used herein, “alkenylene” means a straight or branched chaindi-radical chemical group containing only carbon and hydrogen andcontaining at least one carbon-carbon double bond that is attached tothe rest of the molecule via two points of attachment. In someembodiments, the alkenylene group has from 2 to 20 carbon atoms,although the present definition also covers the occurrence of the termalkenylene where no numerical range is designated. The alkenylene groupmay also be a medium size alkenylene having 2 to 9 carbon atoms. Thealkenylene group could also be a lower alkenylene having 2 to 4 carbonatoms. The alkenylene group may be designated as “C₂₋₄ alkenylene” orsimilar designations. By way of example only, “C₂₋₄alkenylene” indicatesthat there are two to four carbon atoms in the alkenylene chain, i.e.,the alkenylene chain is selected from the group consisting ofethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl,prop-2-en-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene,but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl,but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl,2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene,1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene,3-methyl-propenylene, 2-methyl-propen-1,1-diyl, and2,2-dimethyl-ethen-1,1-diyl. Unless indicated to the contrary, the term“alkenylene” refers to a group that is not further substituted.

As used herein, “aromatic” means a ring or ring system having aconjugated pi electron system and includes both carbocyclic aromatic(e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). Theterm includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of atoms) groups provided that the entire ringsystem is aromatic.

As used herein, “aryl” means an aromatic ring or ring system (i.e., twoor more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. In some embodiments, the aryl group hasfrom 6 to 18 carbon atoms, although the present definition also coversthe occurrence of the term “aryl” where no numerical range isdesignated. In some embodiments, the aryl group has from 6 to 10 carbonatoms. The aryl group may be designated as “C₆₋₁₀ aryl,” “C₆-C₁₀ aryl,”or similar designations. Examples of aryl groups include, but are notlimited to, phenyl, naphthyl, azulenyl, and anthracenyl. In someembodiments, the term “aryl” refers to phenyl. Unless indicated to thecontrary, the term “aryl” refers to a group that is not furthersubstituted

As used herein, “aryloxy” and “arylthio” mean moieties of the formulasRO— and RS—, respectively, in which R is an aryl as is defined above,such as “C₆₋₁₀ aryloxy” or “C₆₋₁₀ arylthio” and the like, including butnot limited to phenyloxy and phenylthio.

As used herein “aralkyl” or “arylalkyl” means an aryl group connected,as a substituent, via an alkylene group, such as “C₇₋₁₄ aralkyl” and thelike, including, but not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, and the like. In some embodiments, the alkylene group isa lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “heteroaryl” means an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. In some embodiments, the heteroaryl group hasfrom 5 to 18 ring members (i.e., the number of atoms making up the ringbackbone, including carbon atoms and heteroatoms), although the presentdefinition also covers the occurrence of the term “heteroaryl” where nonumerical range is designated. In some embodiments, the heteroaryl grouphas from 5 to 10 ring members or from 5 to 7 ring members. Theheteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10membered heteroaryl,” or similar designations. Examples of heteroarylrings include, but are not limited to, furyl, thienyl, phthalazinyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, andbenzothienyl. Unless indicated to the contrary, the term “hereoaryl”refers to a group that is not further substituted.

As used herein, “heteroaralkyl” or “heteroarylalkyl” means heteroarylgroup connected, as a substituent, via an alkylene group. Examplesinclude but are not limited to 2-thienylmethyl, 3-thienylmethyl,furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl,isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene groupis a lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ringsystem containing only carbon atoms in the ring system backbone. Whenthe carbocyclyl is a ring system, two or more rings may be joinedtogether in a fused, bridged or spiro-connected fashion. Carbocyclylsmay have any degree of saturation provided that at least one ring in aring system is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. In some embodiments, the carbocyclylgroup has from 3 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term “carbocyclyl” where no numericalrange is designated. The carbocyclyl group may also be a medium sizecarbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group couldalso be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl groupmay be designated as “C₃₋₆ carbocyclyl” or similar designations.Examples of carbocyclyl rings include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, andspiro[4.4]nonanyl. Unless indicated to the contrary, the term“carbocyclyl” refers to a group that is not further substituted

As used herein, “(carbocyclyl)alkyl” means a carbocyclyl groupconnected, as a substituent, via an alkylene group, such as “C₄₋₁₀(carbocyclyl)alkyl” and the like, including but not limited to,cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl,cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl,and the like. In some cases, the alkylene group is a lower alkylenegroup.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system, according to any of the embodiments set forth above forcarbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” means a carbocyclyl ring or ring systemhaving at least one double bond, wherein no ring in the ring system isaromatic, and according to any of the embodiments set forth above forcarbocyclyl. An example is cyclohexenyl.

As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ringsystem containing at least one heteroatom in the ring backbone.Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. In some embodiments, the heterocyclyl group has from3 to 20 ring members (i.e., the number of atoms making up the ringbackbone, including carbon atoms and heteroatoms), although the presentdefinition also covers the occurrence of the term “heterocyclyl” whereno numerical range is designated. The heterocyclyl group may also be amedium size heterocyclyl having 3 to 10 ring members. The heterocyclylgroup could also be a heterocyclyl having 3 to 6 ring members. Theheterocyclyl group may be designated as “3-6 membered heterocyclyl” orsimilar designations. In preferred six membered monocyclicheterocyclyls, the heteroatom(s) are selected from one up to three of O,N or S, and in preferred five membered monocyclic heterocyclyls, theheteroatom(s) are selected from one or two heteroatoms selected from O,N, or S. Examples of heterocyclyl rings include, but are not limited to,azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline.

As used herein, “(heterocyclyl)alkyl” means a heterocyclyl groupconnected, as a substituent, via an alkylene group. Examples include,but are not limited to, imidazolinylmethyl and indolinylethyl.

An “acyl” group refers to a —C(═O)R, wherein R is hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocycyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, asdefined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, asdefined herein.

A “sulfonyl” group refers to an “—SO₂R” group in which R is selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, asdefined herein.

An “S-sulfonamido” group refers to a “—SO₂NRARB” group in which R_(A)and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “N-sulfonamido” group refers to a “—N(R_(A))SO₂R_(B)” group in whichR_(A) and R_(b) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “O-carbamyl” group refers to a “—OC(═O)NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “N-carbamyl” group refers to an “—N(R_(A))C(═O)OR_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “O-thiocarbamyl” group refers to a “—OC(═S)NR_(A)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “N-thiocarbamyl” group refers to an “—N(R_(A))C(═S)OR_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “N-amido” group refers to a “—N(R_(A))C(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocycyl, as defined herein. Anon-limiting example includes free amino (i.e., —NH₂).

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈alkoxyalkyl” and the like.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substituents independently selected fromC₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), C₃-C₇-carbocyclyl-C₁-C₆-alkyl(optionally substituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10 membered heterocycyl(optionally substituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10 memberedheterocycyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), halo, cyano, hydroxy,C₁-C₆alkoxy, C₁-C₆alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy (optionallysubstituted with halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy), C₃-C₇ carbocyclyloxy (optionally substituted withhalo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),3-10 membered heterocyclyl-oxy (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10membered heteroaryl-oxy (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkoxy (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10membered heterocyclyl-C₁-C₆-alkoxy (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),aryl(C₁-C₆)alkoxy (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkoxy (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), sulfhydryl(mercapto), halo(C₁-C₆)alkyl (e.g., —CF3), halo(C₁-C₆)alkoxy (e.g.,—OCF₃), C₁-C₆alkylthio, arylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), C₃-C₇carbocyclylthio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10 memberedheterocyclyl-thio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl-thio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 3-10membered heterocyclyl-C₁-C₆-alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy),aryl(C₁-C₆)alkylthio (optionally substituted with halo, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkylthio (optionally substituted with halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy), amino,amino(C₁-C₆)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfinyl, sulfonyl, and oxo (═O). Wherever a group isdescribed as “optionally substituted” that group can be substituted withthe above substituents.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as —AE—or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

A “sweetener”, “sweet flavoring agent”, “sweet flavor entity”, or “sweetcompound” herein refers to a compound or ingestibly acceptable saltthereof that elicits a detectable sweet flavor in a subject, e.g., acompound that activates a T1R2/T1R3 receptor in vitro.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. For example,reference to “a substituent” encompasses a single substituent as well astwo or more substituents, and the like.

As used herein, “for example,” “for instance,” “such as,” or “including”are meant to introduce examples that further clarify more generalsubject matter. Unless otherwise expressly indicated, such examples areprovided only as an aid for understanding embodiments illustrated in thepresent disclosure, and are not meant to be limiting in any fashion. Nordo these phrases indicate any kind of preference for the disclosedembodiment.

As used herein, “comprise” or “comprises” or “comprising” or “comprisedof” refer to groups that are open, meaning that the group can includeadditional members in addition to those expressly recited. For example,the phrase, “comprises A” means that A must be present, but that othermembers can be present too. The terms “include,” “have,” and “composedof” and their grammatical variants have the same meaning. In contrast,“consist of” or “consists of” or “consisting of” refer to groups thatare closed. For example, the phrase “consists of A” means that A andonly A is present.

As used herein, “optionally” means that the subsequently describedevent(s) may or may not occur. In some embodiments, the optional eventdoes not occur. In some other embodiments, the optional event does occurone or more times.

As used herein, “or” is to be given its broadest reasonableinterpretation, and is not to be limited to an either/or construction.Thus, the phrase “comprising A or B” means that A can be present and notB, or that B is present and not A, or that A and B are both present.Further, if A, for example, defines a class that can have multiplemembers, e.g., A₁ and A₂, then one or more members of the class can bepresent concurrently.

As used herein, certain monovalent or polyvalent groups having only asingle atom may be referred to by the name of the atom. For example, insome instances, the substituent “—H” may be referred to as “hydrogen” or“a hydrogen atom,” or the substituent “—F” may be referred to as“fluorine” or “a fluorine atom.”

Points of attachment for groups are generally indicated by a terminaldash (-) or by an asterisk (*). For example, a group such as *—CH₂—CH₃or —O₂—CH₃ both represent an ethyl group.

Other terms are defined in other portions of this description, eventhough not included in this subsection.

Antagonists of HT2R54 and Synthesis

In a first aspect, the disclosure provides compounds of formula (I):

or a salt thereof, wherein:

-   -   X¹ and X² are each independently an oxygen atom or        >C(R^(2A))(R^(2B));    -   X³ is a direct bond or >C(R^(2C))(R^(2D));    -   X⁴ is >C(R^(2E))(R^(2F));    -   R^(A) is a halogen atom, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl,        C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, or (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R¹ is a halogen atom, —C(O)—R^(IA), —C(O)—O—R^(1A), —O—R^(1A),        —O—C(O)—R^(1A), or C₁₋₆alkyl, where the alkyl group is        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Y);    -   R¹ is a hydrogen atom or C₁₋₆alkyl, wherein the alkyl group is        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Y);    -   R^(1X) is a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, and (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R^(1Z) is a halogen atom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, (C₁₋₆alkoxy)-C₁₋₆alkyl, C₁₋₆alkyl, and        C₂₋₆alkenyl;    -   R² is —N(R⁵)(R⁶); or    -   R² is

or

R² is a hydrogen atom, a halogen atom, C₃₋₁₀cycloalkyl, C₂₋₁₄heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the carbocyclyl,heterocyclyl, aryl, and heteroaryl are each optionally substituted oneor more times by substituents selected independently from the groupconsisting of R^(1Z);

-   -   X⁵ is >NR^(2G);    -   X⁶ is C₁₋₆alkylene, which is optionally substituted one or more        times by substituents selected independently from the group        consisting of R^(1Y); or    -   X⁷ is an oxygen atom, a sulfur atom, >N—R^(2L), or        >C(R²¹)(R^(2K));    -   X⁸, X⁹, X¹⁰, and X¹¹ are each independently a direct bond, an        oxygen atom, a sulfur atom, or >C(R^(2M))(R^(2N)), wherein no        more than one of X⁸, X⁹, X¹⁰, and X¹¹ is a direct bond, and        wherein no more than one of X⁸, X⁹, X¹⁰, and X¹¹ is an oxygen        atom or a sulfur atom;    -   X¹² is an oxygen atom, a sulfur atom, or >N—R^(2L);    -   X¹³ is a direct bond or >NR^(2P);    -   R^(2A), R^(2B), R^(2C), R^(2D), R^(2E), R^(2F), R^(2K), R^(2M),        and R^(2N) are each independently a hydrogen atom, a halogen        atom, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH,        —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl),        —NH—C(O)—(C₁₋₆alkyl), —NH—C(O)—O—(C₁₋₆alkyl),        —C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂,        —S(O)₂—(C₁₋₆alkyl), —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),        —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄        aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, (C₁₋₆alkoxy)-C₁₋₆alkyl; or R^(2A) and        R^(2B), or R^(2C) and R^(2D), or R^(2E) and R^(2F), or R^(2M)        and R^(2N) optionally combine to form an oxo group; or any two        of R^(2M) and R^(2N) attached to adjacent carbon atoms        optionally combine to form a fused ring selected from the group        consisting of phenyl, C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, and C₂₋₅        heterocyclyl, wherein each of the fused rings is optionally        substituted one or more times by substituents selected        independently from R^(1Z);    -   R^(2G) an R^(2P) are each independently a hydrogen atom,        C₁₋₆alkyl, C₁₋₆haloalkyl, or (C₁₋₆alkoxy)-C₁₋₆alkyl;    -   R^(2J) is —R⁴ or —X¹⁴—R⁴;    -   R^(2L) is —C(O)—R³, —C(O)—X¹⁴—R⁴, —C(S)—R³, —C(S)—X¹⁴—R⁴,        —S(O)₂—R³, —S(O)₂—X¹⁴—R⁴, or —X¹⁴—R⁴;    -   X¹⁴ is C₁₋₈alkylene, which is optionally substituted by one or        more times by substituents selected independently from the group        consisting of R^(1Y);    -   R³ is a hydrogen atom, —OH, —NH₂, —O—R^(3B), —NH—R^(3B),        —N(R^(3B))(R^(3C)), —O—C(O)—R^(3B), —NH—C(O)—R^(3B),        —N(R^(3C))—C(O)—R^(3B), C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the carbocyclyl,        heterocyclyl, aryl, and heteroaryl are each optionally        substituted one or more times by substituents selected        independently from R^(3A), wherein any two R^(3A) attached to        adjacent carbon atoms optionally combine to form a fused ring        selected from the group consisting of phenyl, C₂₋₅ heteroaryl,        C₄₋₈cycloalkyl, and C₂₋₅ heterocyclyl, wherein each of the fused        rings is optionally substituted one or more times by        substituents selected independently from R^(1Z), and wherein,        when R^(3B) and R^(3C) are attached to the same nitrogen atom,        R^(3B) and R^(3C) optionally combine with the nitrogen atom to        which they are attached to form a nitrogen-containing C₂₋₆        heterocyclic ring, which is optionally substituted by C₁₋₄alkyl;    -   R^(3A) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—R^(3D), —NH—R^(3D),        —N(R^(3D))(R^(3E)), —C(O)—R^(3D), —O—C(O)—R^(3D),        —NH—C(O)—R^(3D), —C(O)—O—R^(3D), —C(O)—NH—R^(3D),        —C(O)—N(R^(3D))(R^(3E)), —S(O)₂—R^(3D), —O—S(O)₂—R^(3D),        —NH—S(O)₂—R^(3D), —S(O)₂—O—R^(3D), —S(O)₂—NH—R^(3D),        —S(O)₂—N(R^(3D))(R^(3E)), C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀        carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄        heteroaryl, wherein the alkyl and alkenyl are each optionally        substituted one or more times by substituents selected        independently from the group consisting of R^(3Y), and wherein        the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(3Z);    -   R^(3B), R^(3C), R^(3D), and R^(3E) are each independently        C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl        are each optionally substituted one or more times by        substituents selected independently from the group consisting of        R^(3Y), and wherein the carbocyclyl, heterocyclyl, aryl, and        heteroaryl are each optionally substituted one or more times by        substituents selected independently from the group consisting of        R^(3Z);    -   R^(3Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R^(3Z) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,        C₂₋₆haloalkenyloxy, (C₁₋₆alkoxy)-C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein        the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are        each optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R⁴ is a hydrogen atom, a halogen atom, —CN, nitro, oxo, —OH,        —NH₂, —O—R^(4B), —NH—R^(4B), —N(R^(4B))(R^(4C)), C(O)—R^(4B),        —O—C(O)—R^(4B), —NH—C(O)—R^(4B), —N(R^(4C))—C(O)—R^(4B),        —C(O)—O—R^(4B), —C(O)—NH—R^(4B), —C(O)N(R^(4B))(R^(4C)),        —S(O)₂—R^(4D), —O—S(O)₂—R^(4D), —NH—S(O)₂—R^(4D),        —S(O)₂—O—R^(4D), —S(O)₂—NH—R^(4D), —S(O)₂—N(R^(4D))(R^(4E)),        C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄        heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, and        heteroaryl are each optionally substituted one or more times by        substituents selected independently from R^(4A), wherein any two        R^(4A) attached to adjacent carbon atoms optionally combine to        form a fused ring selected from the group consisting of phenyl,        C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, and C₂₋₅ heterocyclyl, wherein        each of the fused rings is optionally substituted one or more        times by substituents selected independently from R^(1Z), and        wherein, when R^(4B) and R^(4C) are attached to the same        nitrogen atom, R^(4B) and R^(4C) optionally combine with the        nitrogen atom to which they are attached to form a        nitrogen-containing C₂₋₆ heterocyclic ring, which is optionally        substituted by C₁₋₄alkyl;    -   R^(4A) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—R^(4D), —NH—R^(4D),        —N(R^(4D))(R^(4E)), —C(O)—R^(4D), —O—C(O)—R^(4D),        —NH—C(O)—R^(4D), —N(R^(4E))—C(O)—R^(4D), —C(O)—O—R^(4D),        —C(O)—NH—R^(4D), —C(O)—N(R^(4D))(R^(4E)), C₁₋₈alkyl,        C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl,        and C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(4Y), and        wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are        each optionally substituted one or more times by substituents        selected independently from R^(4Z).    -   R^(4B), R^(4C), R^(4D), and R^(4E) are each independently        C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl        are each optionally substituted one or more times by        substituents selected independently from R^(4Y), and wherein the        carbocyclyl, heterocyclyl, aryl, and heteroaryl are each        optionally substituted one or more times by substituents        selected independently from R^(4Z);    -   R^(4Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R^(4Z) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        (C₁₋₆alkoxy)-C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl,        C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, and        C₂₋₆haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl,        and heteroaryl groups are each optionally substituted one or        more times by substituents selected independently from the group        consisting of R′;    -   R⁵ is —C(O)—R³, —C(O)—X¹⁴—R⁴, —C(S)—R³, —C(S)—X¹⁴—R⁴, —S(O)₂—R³,        —S(O)₂—X¹⁴—R⁴, or —X¹⁴—R⁴;    -   R⁶ is a hydrogen atom or C₁₋₈alkyl, wherein the alkyl is        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(6Y);    -   R^(6Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H,        —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),        —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl),        —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),        —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),        —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),        —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),        —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,        —O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄        heterocyclyl, C₆₋₁₄ aryl, and C₂₋₁₄ heteroaryl, wherein the        cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each        optionally substituted one or more times by substituents        selected independently from the group consisting of R^(1Z);    -   R⁷ is a hydrogen atom, a halogen atom, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₁₋₆alkoxy, C₁₋₆haloalkoxy, or (C₁₋₆alkyl)-O—C₁₋₆alkyl; and    -   n is 0, 1, or 2.

Various subgenuses, and combinations thereof, of the genus set forthabove are also contemplated as part of the present disclosure.

For example, in some embodiments of the foregoing, X¹ and X² are both anoxygen atom. In some other embodiments of the foregoing, X¹ and X² areboth >C(R^(2A))(R^(2B)).

In some such embodiments, one of R^(2A) and R^(2B) is a hydrogen atom.In some further such embodiments, one of R^(2A) and R^(2B) is a hydrogenatom, and the other of R^(2A) and R^(2B) is a hydrogen atom, a halogenatom (such as a fluorine atom), C₁₋₆alkyl, C₁₋₆ fluoroalkyl, C₁₋₆alkoxy,C₁₋₆ fluoroalkoxy, or —C(O)—(C₁₋₆alkyl). In some further suchembodiments, both R^(2A) and R^(2B) are a hydrogen atom, such that bothX¹ and X² are >CH₂.

In some embodiments of any of the foregoing embodiments, X³ is a directbond, such that X¹ and X⁴ connect directly to form a five-membered fusedring. In some other embodiments of any of the foregoing embodiments, X³is >C(R^(2C))(R^(2D)). In some such embodiments, one of R^(2C) andR^(2D) is a hydrogen atom. In some further such embodiments, one ofR^(2C) and R^(2D) is a hydrogen atom, and the other of R^(2C) and R^(2D)is a hydrogen atom, a halogen atom (such as a fluorine atom), C₁₋₆alkyl,C₁₋₆ fluoroalkyl, C₁₋₆alkoxy, C₁₋₆ fluoroalkoxy, or —C(O)—(C₁₋₆alkyl).In some further such embodiments, both R^(2C) and R^(2D) are a hydrogenatom, such that X³ is >CH₂.

In some other embodiments of any of the foregoing embodiments, one ofR^(2E) and R^(2F) is a hydrogen atom. In some further such embodiments,one of R^(2E) and R^(2F) is a hydrogen atom, and the other of R^(2E) andR^(2F) is a hydrogen atom, a halogen atom (such as a fluorine atom),C₁₋₆alkyl, C₁₋₆ fluoroalkyl, C₁₋₆alkoxy, C₁₋₆ fluoroalkoxy, or—C(O)—(C₁₋₆alkyl). In some further such embodiments, both R^(2E) andR^(2F) are a hydrogen atom, such that X⁴ is >CH₂.

As indicated above, the phenyl portion of the fused ring system informula (I) can optionally have one or two substituents, R^(A). Thus, insome embodiments of any of the foregoing embodiments, n is 0. In someother embodiments of any of the foregoing embodiments, n is 1. In someother embodiments of any of the foregoing embodiments, n is 2.

The substituents, R^(A), can have any suitable value as indicated above.In some embodiments of any of the foregoing embodiments, R^(A) is ahalogen atom, —OH, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl), C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, or (C₁₋₆alkoxy)-C₁₋₆alkyl. In some further suchembodiments, R^(A) is a fluorine atom, a chlorine atom, methyl, ethyl,isopropyl, hydroxyl, methoxy, trifluoroalkyl, or trifluoromethoxy.

The substituent R^(A), can have any suitable value as indicated above.In some embodiments of any of the foregoing embodiments, R^(A) is ahalogen atom, such as a fluorine atom or a chlorine atom. In some suchembodiments, R^(A) is a chlorine atom. In some other embodiments, of anyof the foregoing embodiments, R¹ is —C(O)—R^(1A). In some otherembodiments, of any of the foregoing embodiments, R¹ is —C(O)—O—R^(1A).In some other embodiments, of any of the foregoing embodiments, R¹ is—O—C(O)—R^(1A). In some other embodiments, R¹ is a halogen atom,—O—R^(1A). In any of the foregoing embodiments, R^(1A) is C₁₋₆alkyl,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, etc. In some further such embodiments, R^(1A) is methyl orethyl. In some other embodiments, of any of the foregoing embodiments,R¹ is —C(O)—CH₃. In some other embodiments, of any of the foregoingembodiments, R¹ is —C(O)—O—CH₃. In some other embodiments, of any of theforegoing embodiments, R¹ is —O—C(O)—CH₃. In some other embodiments, R¹is a halogen atom, —O—CH₃. In some other embodiments, of any of theforegoing embodiments, R¹ is C₁₋₆alkyl, which is optionally substitutedone or more times by substituents selected independently from the groupconsisting of R^(1Y). In some further such embodiments, R¹ is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, or hexyl. In some further such embodiments, R¹ is methyl, ethyl,isoptopyl, or propyl. In some even further such embodiments, R¹ ismethyl or ethyl. In some even further such embodiments, R¹ is ethyl.

The variable X⁵ can have any suitable value, as indicated above. In someembodiments of any of the foregoing embodiments, X⁵ is >NR^(2G), whereR^(2G) is a hydrogen atom or C₁₋₆alkyl. In some further suchembodiments, R^(2G) is a hydrogen atom. In some other such embodiments,R^(2G) is methyl or ethyl.

The variable X⁶ can have any suitable value, as indicated above. In someembodiments of any of the foregoing embodiments, X⁶ is —CH₂—. In someother embodiments of any of the foregoing embodiments, X⁶ is —CH₂—CH₂—.In some other embodiments of any of the foregoing embodiments, X⁶ is—CH(CH₃)—. In some other embodiments of any of the foregoingembodiments, X⁶ is —C(CH₃)₂—.

In some embodiments of any of the foregoing embodiments, R² is—N(R⁵)(R⁶). In some further such embodiments, R⁶ is a hydrogen atom. Insome other such embodiments, R⁶ is C₁₋₈alkyl, which is optionallysubstituted one or more times by substituents selected independentlyfrom the group consisting of a halogen atom, —OH, —O—(C₁₋₆alkyl),—NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, and (C₁₋₆alkoxy)-C₁₋₆alkyl. Insome further such embodiments, R⁶ is unsubstituted C₁₋₈alkyl, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, and the like. In some further embodiments, R⁶ is methyl.

In some further embodiments of any of the foregoing embodiments, R⁵ is—C(O)—R³, —C(O)—X¹⁴—R⁴, or —X¹⁴—R⁴. In some further such embodiments, R⁵is —C(O)—R³. In some further such embodiments, R³ is not a hydrogenatom. In some other such embodiments, R⁵ is —C(O)—X¹⁴—R⁴. In somefurther such embodiments, R⁴ is not a hydrogen atom. In some other suchembodiments, R⁵ is —X¹⁴—R⁴. In some further such embodiments, R⁴ is nota hydrogen atom. In some further embodiments of the embodiments setforth in this paragraph, X¹⁴ is an unsubstituted, straight-chain C₁₋₄alkylene group.

In some embodiments of any of the foregoing embodiments, R² is a moietyof either of the following formulas:

where the asterisk indicates the point of attachment of the ring to X⁶.In some such embodiments, R² is a moiety of the first formula. In someother embodiments of the second formula.

In some further embodiments of the embodiments of the precedingparagraph, none of X⁸, X⁹, X¹⁰, or X¹¹ is a direct bond. In some suchembodiments, one of X⁸, X⁹, X¹⁰, or X¹¹ is an oxygen atom or a sulfuratom. In some other such embodiments, none of X⁸, X⁹, X¹⁰, or X¹¹ is anoxygen atom or a sulfur atom. In some embodiments of each of theforegoing embodiments, each R^(2M) is a hydrogen atom. In some suchembodiments, each R^(2N) is a hydrogen atom, a halogen atom, —OH, —NH₂,—C(O)—OH, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—NH—C(O)—O—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl),—C(O)—N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,(C₁₋₆alkoxy)-C₁₋₆alkyl, phenyl, or C₂₋₅ heteroaryl, wherein the phenyland heteroaryl groups are optionally substituted by substituentsselected independently from the group consisting of C₁₋₄alkyl andC₁₋₄alkoxy. In some such embodiments, each R^(2N) is a hydrogen atom.

In some embodiments of any of the foregoing embodiments, X⁷ is an oxygenatom or a sulfur atom. In some such embodiments, X⁷ is an oxygen atom.In some other such embodiments, X⁷ is a sulfur atom.

In some embodiments of any of the foregoing embodiments, X⁷ is N—R^(2L).In such embodiments, R^(2L) can have any suitable value, according tothose set forth above. In some embodiments, R^(2L) is —C(O)—R³. In someother embodiments, R^(2L) is —C(O)—X¹⁴—R⁴. In some other embodiments,R^(2L) is —C(S)—R³. In some other embodiments, R^(2L) is —C(S)—X¹⁴—R⁴.In some other embodiments, R^(2L) is —S(O)₂—R³. In some otherembodiments, R^(2L) is —S(O)₂—X¹⁴—R⁴. In some other embodiments. In somefurther embodiments of any of the foregoing embodiments of thisparagraph, X¹⁴ is an unsubstituted C₁₋₈alkylene group, such as astraight-chain unsubstituted C₁₋₄alkylene group. In some furtherembodiments of any of the foregoing embodiments of this paragraph, R³ isnot a hydrogen atom. In some further embodiments of any of the foregoingembodiments of this paragraph, R⁴ is not a hydrogen atom.

In some embodiments of any of the foregoing embodiments, X⁷ is>C(R^(2J))(R^(2K)). In such embodiments, R^(2J) and R^(2K) can have anysuitable values, as set forth above. In some such embodiments, R^(2K) isa hydrogen atom. In some other such embodiments, R^(2K) is a C₁₋₆alkylgroup, such as methyl, ethyl, or isopropyl. In some further suchembodiments, R^(2K) is methyl. In some embodiments, R^(2J) is —R⁴. Insome other embodiments, R^(2J) is X¹⁴—R⁴. In some further embodiments ofany of the foregoing embodiments of this paragraph, X¹⁴ is anunsubstituted C₁₋₈alkylene group, such as a straight-chain unsubstitutedC₁₋₄alkylene group. In some further embodiments of any of the foregoingembodiments of this paragraph, R⁴ is not a hydrogen atom.

In some embodiments of any of the foregoing embodiments, R² is a moietyof either of the following formulas:

where the asterisk indicates the point of attachment to X⁶. In some suchembodiments, R² is a moiety of the first formula. In some otherembodiments of the second formula.

In some further embodiments of the embodiments of the precedingparagraph, none of X⁸, X⁹, X¹⁰, or X¹¹ is a direct bond. In some suchembodiments, one of X⁸, X⁹, X¹⁰, or X¹¹ is an oxygen atom or a sulfuratom. In some other such embodiments, none of X⁸, X⁹, X¹⁰, or X¹¹ is anoxygen atom or a sulfur atom. In some embodiments of each of theforegoing embodiments, each R^(2M) is a hydrogen atom. In some suchembodiments, each R^(2N) is a hydrogen atom, a halogen atom, —OH, —NH₂,—C(O)—OH, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—NH—C(O)—O—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl),—C(O)—N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,(C₁₋₆alkoxy)-C₁₋₆alkyl, phenyl, or C₂₋₅ heteroaryl, wherein the phenyland heteroaryl groups are optionally substituted by substituentsselected independently from the group consisting of C₁₋₄alkyl andC₁₋₄alkoxy. In some such embodiments, each R^(2N) is a hydrogen atom.

In some embodiments of any of the foregoing embodiments, X¹² is anoxygen atom or a sulfur atom. In some such embodiments, X¹² is an oxygenatom. In some other such embodiments, X¹² is a sulfur atom.

In some embodiments of any of the foregoing embodiments, X¹² is>N—R^(2L). In such embodiments, R^(2L) can have any suitable value,according to those set forth above. In some embodiments, R^(2L) is—C(O)—R³. In some other embodiments, R^(2L) is —C(O)—X¹⁴—R⁴. In someother embodiments, R^(2L) is —C(S)—R³. In some other embodiments, R^(2L)is —C(S)—X¹⁴—R⁴. In some other embodiments, R^(2L) is —S(O)₂—R³. In someother embodiments, R^(2L) is —S(O)₂—X¹⁴—R⁴. In some other embodiments,R^(2L) is —X¹⁴—R⁴. In some further embodiments of any of the foregoingembodiments of this paragraph, X¹⁴ is an unsubstituted C₁₋₈alkylenegroup, such as a straight-chain unsubstituted C₁₋₄alkylene group. Insome further embodiments of any of the foregoing embodiments of thisparagraph, R³ is not a hydrogen atom. In some further embodiments of anyof the foregoing embodiments of this paragraph, R⁴ is not a hydrogenatom.

The variable X¹³ can have any suitable value, as indicated above. Insome embodiments, X¹³ is a direct bond, which means that the carbon atomof the ring bonds directly to X⁶. In some other embodiments, X¹³ is>NR^(2P). The variable R^(2P) can have any suitable value, as indicatedabove. In some embodiments, R^(2P) is a hydrogen atom. In some otherembodiments, R^(2P) is C₁₋₆alkyl, such as methyl, ethyl, or isopropyl.In some further such embodiments, R^(2P) is methyl or ethyl.

The variable R⁷ can have any suitable value, as indicated above. In someembodiments, R⁷ is a hydrogen atom. In some other embodiments, R⁷ is ahalogen atom, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, or(C₁₋₆alkyl)-O—C₁₋₆alkyl. In some further embodiments, R⁷ is methyl,trifluoromethyl, methoxy, trifluoromethoxy, 2-methoxyethyl, ormethoxymethyl.

In some embodiments, the compound is any compound whose structure is setforth in any of Tables 2-9, or a salt thereof.

In some further embodiments of any of the foregoing embodiments, thesalt is a comestibly acceptable salt. In some other embodiments of anyof the foregoing embodiments, the salt is a pharmaceutically acceptablesalt.

A number of the foregoing embodiments recite a halogen atom as a memberof a particular grouping. In some embodiments of any of the foregoingembodiments, the halogen atom is a fluorine atom or a chlorine atom. Insome further such embodiments, the halogen atom is a fluorine atom.

A number of the foregoing embodiments recite an aryl group as a memberof a particular group. In some embodiments of any of the foregoingembodiments, the aryl group is a phenyl group, unsubstituted orsubstituted as indicated.

A number of the foregoing embodiments recite a carbocyclyl group as amember of a particular group. In some embodiments of any of theforegoing embodiments, the carbocyclyl group is a cycloalkyl group,unsubstituted or substituted as indicated, and having the same range ofcarbon numbers. In some further such embodiments, any carbocyclyl orcycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcyclopentyl, unsubstituted or substituted as indicated.

A number of the foregoing embodiments recite a heteroaryl group as amember of a particular group. In some further such embodiments, any suchheteroaryl group is pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl,pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,furazan-3-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, furan-2-yl, furan-3-yl,thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,pyridizin-3-yl, pyridizin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, or pyrazine-2-yl, any of which are optionallysubstituted as indicated. In some further embodiments, the optionalsubstituents on any of the foregoing rings is limited to substituentsselected from the group consisting of methyl, ethyl, isopropyl,hydroxyl, methoxy, a fluorine atom, a chlorine atom, trifluoromethyl,trifluoromethoxy, —NH₂, methylamino, dimethylamino, methylcarbonyl,ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl.

A number of the foregoing embodiments recite a heterocyclyl group as amember of a particular group. In some further such embodiments, any suchheterocyclyl group is pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-3-yl,imidazolidin-4-yl, imidazolidin-5-yl, oxazolidin-2-yl, oxazolidin-3-yl,oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl,isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,isothiazolidin-5-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,thian-2-yl, thian-3-yl, thian-4-yl, 1,4-dioxan-2-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,thiomorpholin-2-yl, thiomorpholin-3-yl, orthiomorpholin-4-yl, any ofwhich are optionally substituted as indicated. In some furtherembodiments, the optional substituents on any of the foregoing rings islimited to substituents selected from the group consisting of methyl,ethyl, isopropyl, hydroxyl, methoxy, a fluorine atom, a chlorine atom,trifluoromethyl, trifluoromethoxy, —NH₂, methylamino, dimethylamino,methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl. Notethat, in some instances, the heterocyclic rings are formed when twosubstituents on a common nitrogen atom combine to form a ring. Incertain embodiments of such instances, the heterocyclic rings arepyrrolidin-1-yl, pyrazolidin-1-yl, imidazolidin-1-yl, oxazolidin-3-yl,isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl,piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or orthiomorpholin-4-yl,any of which are optionally substituted as indicated. In some furtherembodiments, the optional substituents on any of the foregoing rings islimited to substituents selected from the group consisting of methyl,ethyl, isopropyl, hydroxyl, methoxy, a fluorine atom, a chlorine atom,trifluoromethyl, trifluoromethoxy, —NH₂, methylamino, dimethylamino,methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated (e.g., where thestereochemistry of a chiral center is explicitly shown), all suchisomers and mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

In some embodiments, the compounds disclosed herein are capable offorming acid or base salts by virtue of the presence of amino orcarboxyl groups or groups similar thereto. Physiologically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Physiologicallyacceptable salts can be formed using inorganic and organic bases.Inorganic bases from which salts can be derived include, for example,bases that contain sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum, and the like;particularly preferred are the ammonium, potassium, sodium, calcium andmagnesium salts. In some embodiments, treatment of the compoundsdisclosed herein with an inorganic base results in loss of a labilehydrogen from the compound to afford the salt form including aninorganic cation such as Li⁺, Na⁺, Mg²⁺ and Ca²⁺ and the like. Organicbases from which salts can be derived include, for example, primary,secondary, and tertiary amines, substituted amines including naturallyoccurring substituted amines, cyclic amines, basic ion exchange resins,and the like, specifically such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, and ethanolamine.

Any of the above compounds can exist in any suitable form. For example,in some embodiments, the compounds are dissolved or suspended in aliquid carrier, such as an aqueous composition. In some otherembodiments, the compounds are a crystalline, semi-crystalline, oramorphous solid, or may exist as part of a crystalline solvate, such asa crystalline hydrate, or as a co-crystal with another crystallinesolid, such as a crystalline sweetener compound (e.g., erythritol,sucrose, fructose, and the like).

The above compounds can be synthesized in a manner consistent with thatset forth in the Examples below.

Uses and Methods

In a second aspect, the disclosure provides uses of compounds of thefirst aspect, and any embodiments or combinations of embodiments setforth above.

In a related third aspect, the disclosure provides uses of compounds ofthe first aspect, and any embodiments or combinations of embodiments setforth above, to reduce a bitter taste or enhance a sweet taste of acomposition, such as comestible composition or a pharmaceuticalcomposition.

In some embodiments, the uses are uses to uses to reduce a bitter tasteof a comestible composition. In some such embodiments, the comestiblecomposition is a flavored article, such as a food product or a beverageproduct. Bitter taste can arise from a number of different sources. Forexample, products derived from natural sources can often contain bittercompounds. Common non-limiting examples of such bitter compounds arementhol, tannins in tea, coffee, and wine, hop extracts in beer, and thelike. Bitter compounds can also be present in certain fruit andvegetable juices, such as the juice of kale, beets, and the like. Thus,one or more compounds of the first aspect can be introduced to productscontaining such bitter compounds for the purpose of reducing theirperceived bitterness. This, in turn, leads to greater consumption ofsuch materials or a reduction in the amount of caloric sweeteners usedto offset the perception of bitterness in such products. Proteinformulations, such as plant-derived protein isolates are often bitter tothe taste. This, in some embodiments, one of more compounds of the firstaspect are combined with such compounds to reduce the bitter taste ofsuch proteins. Thus, one or more compounds of the first aspect can beincluded in products that may employ such proteins, such as proteinpowders, energy bars, snack foods, and various food items that usenon-animal-derived products as substitutes for cheese, meat, and otherproducts traditionally derived from animal sources. Thus, one or morecompounds of the first aspect can be included in various cheesesubstitutes, meat substitutes, and the like. They can also be includedin products in which protein is added to increase the ratio of proteinto carbohydrates, where the addition of the protein may impart a bittertaste. Additionally, substitutes for salt, MSG, and other savorycompounds can be replaced by healthier alternatives like potassiumchloride (KCl). But these substitutes often impart a bitter taste. Thus,one or more compounds of the first aspect can be used to reduce thisbitter taste when included in low-salt or MSG-free variants oftraditional savory foods, such as potato chips, soup stock,meat-containing products, nuts, and the like. Thus, such compounds canbe used in combination with KCl in such foods. Further, substitutes forcaloric sweeteners, such as various natural or synthetic sweeteners, canimpart a bitter taste when used as substitutes for caloric sweeteners,such as sucrose or fructose. This, in some embodiments, one or morecompounds of the first aspect are used in combination with one or morenon-caloric or low-caloric sweeteners, such as sucralose, saccharine,acesulfame K, aspartame, steviol glycosides, including rebaudiosides,mogrosides, glycyrrhizin, and flavanones, such as naringenin,hesperetin, and their glucosylated derivatives. Further, one or morecompounds of the first aspect can be combined with any othertaste-enhancing compounds, including: sweetness enhancers, such assiratose; umami enhancers, such as ericamide; other bitter tastereduction agents; and sour taste reduction agents.

In some embodiments, the uses are uses to uses to reduce a bitter tasteof a pharmaceutical composition. In this case, the bitterness is causedby certain active pharmaceutical ingredients (APIs) or other excipientsadded to the formulation to enhance the efficacy and delivery of thedrug. At present, various encapsulation strategies are employed to maskthe taste of certain bitter components with drug formulations. In someinstances, however, one could dispense with such sequestrationtechnologies and merely combine the bitter compounds with one or morecompounds of the first aspect to reduce the bitter taste of thepharmaceutical composition. In general, such pharmaceutical compositionsare pharmaceutical composition for oral administration, such as tablets,capsules, elixirs, lozenges, and the like.

In a related fourth aspect, the disclosure provides uses of compounds ofthe first aspect in the manufacture of a product for the reduction ofbitter taste or the enhancement of sweet taste in the product. In someembodiments, the disclosure provides uses of compounds of the firstaspect in the manufacture of a flavored article, such as a flavored foodor beverage product, for the reduction of bitter taste in the product.When incorporated into such products in the manufacturing process, theone or more compounds of the first aspect can be combined with othercompounds in any manner described above for uses of the third aspect. Insome other embodiments, the disclosure provides uses of compounds of thefirst aspect in the manufacture of a medicament for the reduction ofbitter taste in the medicament. When incorporated into such products inthe manufacturing process, the one or more compounds of the first aspectcan be combined with other compounds in any manner described above foruses of the third aspect.

In a related fifth aspect, the disclosure provides uses of compounds ofthe first aspect to antagonize one or more human T2R taste receptors,such as one or more human T2R54 taste receptors. As noted above in thethird and fourth aspects, these uses can involve incorporation intovarious food products and pharmaceutical products, according to any ofthe embodiments set forth in connection with those aspects.

In a related sixth aspect, the disclosure provides methods of reducing abitter taste or enhancing a sweet taste of a flavored composition or apharmaceutical composition, the method comprising introducing an amount(such as an effective amount) of one or more compounds of the firstaspect to the flavored composition or the pharmaceutical composition. Insome embodiments, the disclosure provides methods of reducing a bittertaste of a flavored composition, the method comprising introducing anamount (such as an effective amount) of one or more compounds of thefirst aspect to the flavored composition. In some such embodiments, theflavored composition if a food or beverage product. In some otherembodiments, the disclosure provides methods of reducing a bitter tasteof a pharmaceutical composition, the method comprising introducing anamount (such as an effective amount) of one or more compounds of thefirst aspect to the pharmaceutical composition. As noted above in thethird and fourth aspects, these methods can involve incorporation intovarious food products and pharmaceutical products, according to any ofthe embodiments set forth in connection with those aspects. In general,the effective amount is an amount ranging from 5 to 2000 ppm, or from 5to 1000 ppm, or from 5 to 800 ppm, or from 5 to 500 ppm, or from 5 to400 ppm, or from 5 to 300 ppm, or from 5 to 200 ppm, based on the totalweight of the composition. These amounts are also germane to the usesand methods of the preceding aspects.

In a related seventh aspect, the disclosure provides methods ofantagonizing a human T2R receptor, the methods comprising contacting ahuman T2R receptor with one or more compounds of the first aspect. Insome embodiments thereof, the method comprises contacting a humanT2R54receptor with one or more compounds of the first aspect. In someembodiments, the contacting comprises orally ingesting a compositioncomprising one or more compounds of the first aspect. In some suchembodiments, composition is a flavored composition, such as a food orbeverage product. In some other such embodiments, the composition is apharmaceutical composition. As noted above in the third and fourthaspects, these uses can involve incorporation into various food productsand pharmaceutical products, according to any of the embodiments setforth in connection with those aspects. In general, the effective amountis an amount ranging from 5 to 2000 ppm, or from 5 to 1000 ppm, or from5 to 800 ppm, or from 5 to 500 ppm, or from 5 to 400 ppm, or from 5 to300 ppm, or from 5 to 200 ppm, based on the total weight of thecomposition. These amounts are also germane to the uses and methods ofthe preceding aspects.

As noted in the preceding uses and methods, the compounds of the firstaspect are used in various compositions, such as comestible orpharmaceutical compositions. The following details concerningcompositions can be used in combination with any of the compositionsdescribed in the foregoing uses and methods.

Compositions

In certain aspects, the disclosure provides a composition comprising anamount of one or more compounds of the first aspect. In someembodiments, the composition comprises one or more bitter compounds anda bitter-reducing effective amount of one or more compounds of the firstaspect. In some further embodiments, the composition is a pharmaceuticalcomposition and the bitter compounds are one or more pharmaceuticalcompounds, such as active pharmaceutical ingredients (APIs). In someother embodiments, the composition is a flavored composition, such as afood or beverage product, and the bitter compounds are artificialsweeteners, caffeine, proteins (such as plant proteins), amino acids,compounds derived from natural plant extracts, and the like.

In some embodiments, compounds as disclosed and described herein,individually or in combination, can be used for one or more methods suchas modifying receptor function associated with chemosensory orchemosensory related sensation or reaction.

Some embodiments provide a method of modulating a chemosensory receptorthat includes modulating the activity, structure, function, and/ormodification of a chemosensory receptor as well as modulating, treating,or taking prophylactic measure of a condition, e.g., physiological orpathological condition, associated with a chemosensory receptor. Ingeneral, a physiological or pathological condition associated with achemosensory receptor includes a condition, disease, or disorderassociated with the chemosensory receptor and/or its ligand, e.g.;gastrointestinal disorders, metabolic disorders, functionalgastrointestinal disorders, etc. In one embodiment, the method includesincreasing or enhancing sweet flavor. In another embodiment, the methodincludes modulating a sweet receptor and/or its ligand expressed in aplace of the body other than the taste buds, such as an internal organ.

In general, compounds as disclosed and described herein, individually orin combination, can be provided in a composition, such as, e.g., aningestible (or comestible) composition. In some embodiments, compoundsas disclosed and described herein, individually or in combination,reduce the perception of bitter taste associated with certain bittercompounds in a composition. In another embodiment, compounds asdisclosed and described herein, individually or in combination, canincrease or enhance the sweet taste of a composition by contacting thecomposition thereof with the compounds as disclosed and described hereinto form a modified composition. In another embodiment, compounds asdisclosed and described herein, individually or in combination, can bein a composition that modulates the bitterness receptors and/or theirligands expressed in the body other than in the taste buds, such as thehuman T2R receptors, for example, T2R54.

Some embodiments provide an ingestible composition, comprising one ormore compounds of the first aspect and one or more bitter compounds. Insome embodiments, the composition further comprises a vehicle. In someembodiments, the vehicle is water. In some further embodiments, thecompositions can include one or more natural or artificial sweeteners.In some embodiments, the compound may be present at a concentration ator below its sweetness recognition threshold. In some embodiments, thesweetener is present in an amount from about 0.1% to about 12% byweight. In some embodiments, the sweetener is present in an amount fromabout 0.2% to about 10% by weight. In some embodiments, the sweetener ispresent in an amount from about 0.3% to about 8% by weight. In someembodiments, the sweetener is present in an amount from about 0.4% toabout 6% by weight. In some embodiments, the sweetener is present in anamount from about 0.5% to about 5% by weight. In some embodiments, thesweetener is present in an amount from about 1% to about 2% by weight.In some embodiments, the sweetener is present in an amount from about0.1% to about 5% by weight. In some embodiments, the sweetener ispresent in an amount from about 0.1% to about 4% by weight. In someembodiments, the sweetener is present in an amount from about 0.1% toabout 3% by weight. In some embodiments, the sweetener is present in anamount from about 0.1% to about 2% by weight. In some embodiments, thesweetener is present in an amount from about 0.1% to about 1% by weight.In some embodiments, the sweetener is present in an amount from about0.1% to about 0.5% by weight. In some embodiments, the sweetener ispresent in an amount from about 0.5% to about 10% by weight. In someembodiments, the sweetener is present in an amount from about 2% toabout 8% by weight. In some embodiments, the sweetener may be commonsaccharide sweeteners, e.g., sucrose, fructose, glucose, and sweetenercompositions comprising natural sugars, such as corn syrup (includinghigh fructose corn syrup) or other syrups or sweetener concentratesderived from natural fruit and vegetable sources; rare natural sugarsincluding D-allose, D-psicose, L-ribose, D-tagatose, L-glucose,L-fucose, L-arbinose, D-turanose, and D-leucrose; semi-synthetic “sugaralcohol” sweeteners such as erythritol, isomalt, lactitol, mannitol,sorbitol, xylitol, maltodextrin, and the like; and artificial sweetenerssuch as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, andalitame. In some embodiments, the sweetener may be selected from thegroup consisting of cyclamic acid, mogroside, tagatose, maltose,galactose, mannose, sucrose, fructose, lactose, neotame and otheraspartame derivatives, glucose, D-tryptophan, glycine, maltitol,lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A and other sweetStevia-based glycosides, carrelame and other guanidine-based sweeteners.In some embodiments, the sweetener may combinations of two or moresweeteners as disclosed herein. In some embodiments, the sweetener maycombinations of two, three, four or five sweeteners as disclosed herein.In some embodiments, the sweetener may be a sugar. In some embodiments,the sweetener may be a combination of one or more sugars and othernatural and artificial sweeteners. In some embodiments, the sweetener isa sugar. In some embodiments, the sugar is cane sugar. In someembodiments, the sugar is beet sugar. In some embodiments, the sugar maybe sucrose, fructose, glucose or combinations thereof. In someembodiments, the sugar may be sucrose. In some embodiments, the sugarmay be a combination of fructose and glucose. In some embodiments, thesugar may be a combination of about 55% fructose and about 42% glucose.In some embodiments, the sugar may be a combination of about 42%fructose and about 53% glucose. In some embodiments, the sugar may be acombination of about 90% fructose and about 10% glucose. In someembodiments, the sweetener may be a rare sugar. In some embodiments, therare sugar is selected from the group consisting of D-allose, D-psicose,L-ribose, D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose,D-leucrose and combinations thereof. In some embodiments, the rare sugaris D-psicose. In some embodiments, the rare sugar is D-tagatose. In someembodiments, the sweetener is an artificial sweetener. In someembodiments, the artificial sweetener may be sucralose. In someembodiments, the sweetener is rebaudiosode A or other sweet Stevia-basedglycosides, such as glucosylated steviol glycosides.

In some embodiments, an ingestible composition may be a beverage. Insome embodiments, the beverage may be selected from the group consistingof enhanced sparkling beverages, colas, lemon-lime flavored sparklingbeverages, orange flavored sparkling beverages, grape flavored sparklingbeverages, strawberry flavored sparkling beverages, pineapple flavoredsparkling beverages, ginger-ales, root beers, fruit juices,fruit-flavored juices, juice drinks, nectars, vegetable juices,vegetable-flavored juices, sports drinks, energy drinks, enhanced waterdrinks, enhanced water with vitamins, near water drinks, coconut waters,tea type drinks, coffees, cocoa drinks, beverages containing milkcomponents, beverages containing cereal extracts and smoothies. In someembodiments, the beverage may be a soft drink.

In some embodiments, one or more compounds as described herein and oneor more sweetener as described herein may be included in a food orbeverage product, wherein the food or beverage product may additionallycomprise:

-   -   acids, including, for example citric acid, phosphoric acid,        ascorbic acid, sodium acid sulfate, lactic acid, or tartaric        acid;    -   bitter ingredients, including, for example caffeine, quinine,        green tea, catechins, polyphenols, green robusta coffee extract,        green coffee extract, protein isolate (such as whey protein        isolate or soy protein isolate), or potassium chloride;    -   coloring agents, including, for example caramel color, Red #40,        Yellow #5, Yellow #6, Blue #1, Red #3, purple carrot, black        carrot juice, purple sweet potato, vegetable juice, fruit juice,        beta carotene, turmeric curcumin, or titanium dioxide;        preservatives, including, for example sodium benzoate, potassium        benzoate, potassium sorbate, sodium metabisulfate, sorbic acid,        or benzoic acid;    -   antioxidants including, for example ascorbic acid, calcium        disodium EDTA, alpha tocopherols, mixed tocopherols, rosemary        extract, grape seed extract, resveratrol, or sodium        hexametaphosphate;    -   vitamins or functional ingredients including, for example        resveratrol, Co-Q10, omega 3 fatty acids, theanine, choline        chloride (citocoline), fibersol, inulin (chicory root), taurine,        panax ginseng extract, guanana extract, ginger extract,        L-phenylalanine, L-carnitine, L-tartrate, D-glucoronolactone,        inositol, bioflavonoids, Echinacea, ginko biloba, yerba mate,        flax seed oil, garcinia cambogia rind extract, white tea        extract, ribose, milk thistle extract, grape seed extract,        pyrodixine HCl (vitamin B6), cyanoobalamin (vitamin B12),        niacinamide (vitamin B3), biotin, calcium lactate, calcium        pantothenate (pantothenic acid), calcium phosphate, calcium        carbonate, chromium chloride, chromium polynicotinate, cupric        sulfate, folic acid, ferric pyrophosphate, iron, magnesium        lactate, magnesium carbonate, magnesium sulfate, monopotassium        phosphate, monosodium phosphate, phosphorus, potassium iodide,        potassium phosphate, riboflavin, sodium sulfate, sodium        gluconate, sodium polyphosphate, sodium bicarbonate, thiamine        mononitrate, vitamin D3, vitamin A palmitate, zinc gluconate,        zinc lactate, or zinc sulphate;    -   clouding agents, including, for example ester gun, brominated        vegetable oil (BVO), or sucrose acetate isobutyrate (SAIB);    -   buffers, including, for example sodium citrate, potassium        citrate, or salt;    -   flavors, including, for example propylene glycol, ethyl alcohol,        glycerine, gum Arabic (gum acacia), maltodextrin, modified corn        starch, dextrose, natural flavor, natural flavor with other        natural flavors (natural flavor WONF), natural and artificial        flavors, artificial flavor, silicon dioxide, magnesium        carbonate, or tricalcium phosphate; and    -   stabilizers, including, for example pectin, xanthan gum,        carboxylmethylcellulose (CMC), polysorbate 60, polysorbate 80,        medium chain triglycerides, cellulose gel, cellulose gum, sodium        caseinate, modified food starch, gum Arabic (gum acacia), or        carrageenan.

In some further embodiments, the compositions may contain one or moreflavonones, or glucosylated derivatives thereof. Non-limiting examplesinclude blumeatin, butin, eriodictyol, hesperetin, hesperidin,homoeriodictyol, isosakuranetin, naringenin, naringin, pinocembrin,poncirin, sakuranetin, sakuranin, sterubin, pinostrobin, or glucosylatedderivatives thereof.

Some embodiments provide a method of enhancing sweetness of a sweetener,comprising combining one or more compounds of the first aspect with thesweetener. In some embodiments, the sweetener may be common saccharidesweeteners, e.g., sucrose, fructose, glucose, and sweetener compositionscomprising natural sugars, such as corn syrup (including high fructosecorn syrup) or other syrups or sweetener concentrates derived fromnatural fruit and vegetable sources; rare natural sugars includingD-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose,L-arbinose, D-turanose, and D-leucrose; semi-synthetic “sugar alcohol”sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol,xylitol, maltodextrin, and the like; and artificial sweeteners such asaspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame.In some embodiments, the sweetener may be selected from the groupconsisting of cyclamic acid, mogroside, tagatose, maltose, galactose,mannose, sucrose, fructose, lactose, neotame and other aspartamederivatives, glucose, D-tryptophan, glycine, maltitol, lactitol,isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A and other sweetStevia-based glycosides, carrelame and other guanidine-based sweeteners.In some embodiments, the sweetener may combinations of two or moresweeteners as disclosed herein. In some embodiments, the sweetener maycombinations of two, three, four or five sweeteners as disclosed herein.In some embodiments, the sweetener may be a sugar. In some embodiments,the sweetener may be a combination of one or more sugars and othernatural and artificial sweeteners. In some embodiments, the sweetener isa sugar. In some embodiments, the sugar is cane sugar. In someembodiments, the sugar is beet sugar. In some embodiments, the sugar maybe sucrose, fructose, glucose or combinations thereof (for example, highfructose corn syrup). In some embodiments, the sugar may be sucrose. Insome embodiments, the sugar may be a combination of fructose andglucose. In some embodiments, the sugar may be a combination of about55% fructose and about 42% glucose. In some embodiments, the sugar maybe a combination of about 42% fructose and about 53% glucose. In someembodiments, the sugar may be a combination of about 90% fructose andabout 10% glucose. In some embodiments, the sweetener may be a raresugar. In some embodiments, the rare sugar is selected from the groupconsisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose,L-fucose, L-arbinose, D-turanose, D-leucrose and combinations thereof.In some embodiments, the rare sugar is D-psicose. In some embodiments,the rare sugar is D-tagatose. In some embodiments, the sweetener is anartificial sweetener. In some embodiments, the artificial sweetener maybe sucralose.

In one embodiment, compounds as disclosed and described herein,individually or in combination, can be used at its ligand enhancingconcentrations, e.g., very low concentrations on the order of a fewparts per million, in combination with one or more known sweeteners,natural or artificial, so as to reduce the concentration of the knownsweetener required to prepare an ingestible composition having thedesired degree of sweetness.

In one embodiment, compounds as disclosed and described herein,individually or in combination, can enhance the sweetness of a sweetenerunder a broad range of pH, e.g., from lower pH to neutral pH. The lowerand neutral pH includes, but is not limited to, a pH from about 2.5 toabout 8.5; from about 3.0 to about 8.0; from about 3.5 to about 7.5; andfrom about 4.0 to about 7. In certain embodiments, compounds asdisclosed and described herein, individually or in combination, canenhance the perceived sweetness of a fixed concentration of a sweetenerin taste tests at a compound concentration of about 500 μM, 200 μM, 100μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, or 10 μM at both low to neutralpH value. In certain embodiments, the enhancement factor of thecompounds as disclosed and described herein, individually or incombination, at the lower pH is substantially similar to the enhancementfactor of the compounds at neutral pH. Such consistent sweet enhancingproperty under a broad range of pH allow a broad use in a wide varietyof foods and beverages of the compounds as disclosed and describedherein, individually or in combination. In some embodiments, thesweetener may be common saccharide sweeteners, e.g., sucrose, fructose,glucose, and sweetener compositions comprising natural sugars, such ascorn syrup (including high fructose corn syrup) or other syrups orsweetener concentrates derived from natural fruit and vegetable sources;rare natural sugars including D-allose, D-psicose, L-ribose, D-tagatose,L-glucose, L-fucose, L-arbinose, D-turanose, and D-leucrose;semi-synthetic “sugar alcohol” sweeteners such as erythritol, isomalt,lactitol, mannitol, sorbitol, xylitol, maltodextrin, and the like; andartificial sweeteners such as aspartame, saccharin, acesulfame-K,cyclamate, sucralose, and alitame. In some embodiments, the sweetenermay be selected from the group consisting of cyclamic acid, mogroside,tagatose, maltose, galactose, mannose, sucrose, fructose, lactose,neotame and other aspartame derivatives, glucose, D-tryptophan, glycine,maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS),hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A andother sweet Stevia-based glycosides, carrelame and other guanidine-basedsweeteners. In some embodiments, the sweetener may combinations of twoor more sweeteners as disclosed herein. In some embodiments, thesweetener may combinations of two, three, four or five sweeteners asdisclosed herein. In some embodiments, the sweetener may be a sugar. Insome embodiments, the sweetener may be a combination of one or moresugars and other natural and artificial sweeteners. In some embodiments,the sweetener may be a sugar. In some embodiments, the sugar is canesugar. In some embodiments, the sugar is beet sugar. In someembodiments, the sweetener may be a combination of one or more sugarsand other natural and artificial sweeteners. In some embodiments, thesugar may be sucrose, fructose, glucose or combinations thereof (forexample, high fructose corn syrup). In some embodiments, the sugar maybe sucrose. In some embodiments, the sugar may be a combination offructose and glucose. In some embodiments, the sugar may be acombination of about 55% fructose and about 42% glucose. In someembodiments, the sugar may be a combination of about 42% fructose andabout 53% glucose. In some embodiments, the sugar may be a combinationof about 90% fructose and about 10% glucose. In some embodiments, thesweetener may be a rare sugar. In some embodiments, the rare sugar isselected from the group consisting of D-allose, D-psicose, L-ribose,D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose, D-leucrose andcombinations thereof. In some embodiments, the rare sugar is D-psicose.In some embodiments, the rare sugar is D-tagatose. In some embodiments,the sweetener is an artificial sweetener. In some embodiments, theartificial sweetener is sucralose.

Sweeteners have a wide range of chemically distinct structures and hencepossess varying properties, such as, without limitation, odor, flavor,mouthfeel, and aftertaste.

In at least one aspect, the disclosure provides formulations comprisingone or more compounds of the first aspect (of any of the embodiments setforth above, or as any individual compounds of Tables 2-9, orcombinations thereof) and one or more sweeteners, such as natural orartificial sweeteners. In some such embodiments, the formulationscomprise the one or more sweeteners at concentrations below theconcentration of optimal sweetness, if used alone or without the hT2R54antagonists disclosed herein.

Any suitable natural or artificial sweeteners, or any combinationsthereof, may be used. Natural or artificial sweeteners for use in theformulation comprising a sweetener in combination with a bitternessreducer (i.e., the T2R54 modulators disclosed herein) include but arenot limited to natural or synthetic carbohydrates or carbohydrateanalogues, including monosaccharides, disaccharides, oligosaccharides,and polysaccharides, and including rare sugars, or sugars in either ofthe D- or L-conformations, and include, for example, sucrose, fructose,glucose, L-arabinose, L-fucose, L-glucose, L-ribose, D-arabino-hexulose,psicose, altrose, arabinose, turanose, abequose, allose, abrusoside A,aldotriose, threose, xylose, xylulose, xylo-oligosaccharide (such asxylotriose and xylobiose), lyxose, polydextrose, oligofructose, fucose,galacto-oligosaccharide, galactosamine, galactose,gentio-oligosaccharide (such as gentiobiose, gentiotriose, andgentiotetraose), dextrose, cellobiose, D-leucrose, D-psicose, D-ribose,D-tagatose, trehalose (mycose), neotrehalose, isotrehalose, raffinose,idose, tagatose, melibiose, mannan-oligosaccharide, rhamnose, ribose,ribulose, malto-oligosaccharide (such as maltotriose, maltotetraose,maltopentaose, maltohexaose, and maltoheptaose), maltose, sucroseacetate isobutyrate, dextrose, erythrose, erythrulose, deoxyribose,gulose, ketotriose, lactose, lactulose, kestose, nystose, mannose,sucralose, palatinose, polydextrose, sorbose, sugaridextrose (blendedsugar), or talose, or combinations of any two or more of theaforementioned sweeteners.

The sweetener can also include, for example, sweetener compositionscomprising one or more natural or synthetic carbohydrate, such as cornsyrup, high fructose corn syrup, high maltose corn syrup, glucose syrup,sucralose syrup, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), or other syrups or sweetener concentrates derivedfrom natural fruit and vegetable sources, or semi-synthetic “sugaralcohol” sweeteners such as polyols. Non-limiting examples of polyols insome embodiments include erythritol, maltitol, mannitol, sorbitol,lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerin),threitol, galactitol, palatinose, reduced isomalto-oligosaccharides,reduced xylo-oligosaccharides, reduced gentio-oligosaccharides, reducedmaltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, andthe like, and sugar alcohols or any other carbohydrates or combinationsthereof capable of being reduced which do not adversely affect taste.

The sweetener may be a natural or synthetic sweetener that includes, butis not limited to, agave inulin, agave nectar, agave syrup, amazake,brazzein, brown rice syrup, coconut crystals, coconut sugars, coconutsyrup, date sugar, fructans (also referred to as inulin fiber,fructo-oligosaccharides, or oligo-fructose), green stevia powder, Steviarebaudiana, rebaudioside A, rebaudioside B, rebaudioside C, rebaudiosideD, rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H,rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside N,rebaudioside 0, rebaudioside M and other sweet stevia-based glycosides,stevioside, stevioside extracts, honey, Jerusalem artichoke syrup,licorice root, luo han guo (fruit, powder, or extracts), lucuma (fruit,powder, or extracts), maple sap (including, for example, sap extractedfrom Acer saccharum, Acer nigrum, Acer rubrum, Acer saccharinum, Acerplatanoides, Acer negundo, Acer macrophyllum, Acer grandidentatum, Acerglabrum, Acer mono), maple syrup, maple sugar, walnut sap (including,for example, sap extracted from Juglans cinerea, Juglans nigra, Juglansailatifolia, Juglans regia), birch sap (including, for example, sapextracted from Betula papyrifera, Betula alleghaniensis, Betula lenta,Betula nigra, Betula populifolia, Betula pendula), sycamore sap (suchas, for example, sap extracted from Platanus occidentalis), ironwood sap(such as, for example, sap extracted from Ostrya virginiana), mascobado,molasses (such as, for example, blackstrap molasses), molasses sugar,monatin, monellin, cane sugar (also referred to as natural sugar,unrefined cane sugar, or sucrose), palm sugar, panocha, piloncillo,rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, cassava syrup(also referred to as tapioca syrup), thaumatin, yacon root, malt syrup,barley malt syrup, barley malt powder, beet sugar, cane sugar,crystalline juice crystals, caramel, carbitol, carob syrup, castorsugar, hydrogenated starch hydrolates, hydrolyzed can juice, hydrolyzedstarch, invert sugar, anethole, arabinogalactan, arrope, syrup, P-4000,acesulfame potassium (also referred to as acesulfame K or ace-K),alitame (also referred to as aclame), advantame, aspartame, baiyunoside,neotame, benzamide derivatives, bernadame, canderel, carrelame and otherguanidine-based sweeteners, vegetable fiber, corn sugar, couplingsugars, curculin, cyclamates, cyclocarioside I, demerara, dextran,dextrin, diastatic malt, dulcin, sucrol, valzin, dulcoside A, dulcosideB, emulin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol,glucin, gluconic acid, glucono-lactone, glucosamine, glucoronic acid,glycerol, glycine, glycyphillin, glycyrrhizin, golden sugar, yellowsugar, golden syrup, granulated sugar, gynostemma, hernandulcin,isomerized liquid sugars, jallab, chicory root dietary fiber, kynureninederivatives (including N′-formyl-kynurenine, N′-acetyl-kynurenine,6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, lugduname,guanidine, falernum, mabinlin I, mabinlin II, maltol, maltisorb,maltodextrin, maltotriol, mannosamine, miraculin, mizuame, mogrosides(including, for example, mogroside IV, mogroside V, and neomogroside),mukurozioside, nano sugar, naringin dihydrochalcone, neohesperidinedihydrochalcone, nib sugar, nigero-oligosaccharide, norbu, orgeat syrup,osladin, pekmez, pentadin, periandrin I, perillaldehyde, perillartine,petphyllum, phenylalanine, phlomisoside I, phlorodizin, phyllodulcin,polyglycitol syrups, polypodoside A, pterocaryoside A, pterocaryoside B,rebiana, refiners syrup, rub syrup, rubusoside, selligueain A, shugr,siamenoside I, siraitia grosvenorii, soybean oligosaccharide, Splenda,SRI oxime V, steviol glycoside, steviolbioside, stevioside, strogins 1,2, and 4, sucronic acid, sucrononate, sugar, suosan, phloridzin,superaspartame, tetrasaccharide, threitol, treacle, trilobtain,tryptophan and derivatives (6-trifluoromethyl-tryptophan,6-chloro-D-tryptophan), vanilla sugar, volemitol, birch syrup,aspartame-acesulfame, assugrin, and combinations or blends of any two ormore thereof.

In still other embodiments, the sweetener can be a chemically orenzymatically modified natural high potency sweetener. Modified naturalhigh potency sweeteners include glycosylated natural high potencysweetener such as glucosyl-, galactosyl-, or fructosyl-derivativescontaining 1-50 glycosidic residues. Glycosylated natural high potencysweeteners may be prepared by enzymatic transglycosylation reactioncatalyzed by various enzymes possessing transglycosylating activity. Insome embodiments, the modified sweetener can be substituted orunsubstituted.

Additional sweeteners also include combinations of any two or more ofany of the aforementioned sweeteners. In some embodiments, the sweetenermay comprise combinations of two, three, four or five sweeteners asdisclosed herein. In some embodiments, the sweetener may be a sugar. Insome embodiments, the sweetener may be a combination of one or moresugars and other natural and artificial sweeteners.

One of skill in the art will recognize that any one or more of any ofthe aforementioned sweeteners can be combined in various ratios,amounts, or concentrations to yield a sweetener alone or a combinationof two or more sweeteners, which is then combined with one or moreflavor modifying compound.

One of skill in the art will recognize that the aforementionedsweeteners for use in a formulation comprising one or more sweetener andone or more flavor modifying compound are provided by way of example andare not intended to be limiting.

Some embodiments provide supplements, nutraceuticals, functional foodproducts (e.g., any fresh or processed food claimed to have ahealth-promoting and/or disease-preventing properties beyond the basicnutritional function of supplying nutrients), pharmaceutical product,over the counter (OTC) product, oral care product, cosmetic productssuch as sweetened lip balms, and other personal care products includingcompounds as disclosed and described herein, individually or incombination.

In general, over the counter (OTC) product and oral care productgenerally refer to product for household and/or personal use which maybe sold without a prescription and/or without a visit to a medicalprofessional. Examples of the OTC products include, but are not limitedto Vitamins and dietary supplements; Topical analgesics and/oranesthetic; Cough, cold and allergy remedies; Antihistamines and/orallergy remedies; and combinations thereof. Vitamins and dietarysupplements include, but are not limited to vitamins, dietarysupplements, tonics/bottled nutritive drinks, child-specific vitamins,dietary supplements, any other products of or relating to or providingnutrition, and combinations thereof. Topical analgesics and/oranesthetic include any topical creams/ointments/gels used to alleviatesuperficial or deep-seated aches and pains, e.g. muscle pain; teethinggel; patches with analgesic ingredient; and combinations thereof. Cough,cold and allergy remedies include, but are not limited to decongestants,cough remedies, pharyngeal preparations, medicated confectionery,antihistamines and child-specific cough, cold and allergy remedies; andcombination products. Antihistamines and/or allergy remedies include,but are not limited to any systemic treatments for hay fever, nasalallergies, insect bites and stings. Examples of oral care productinclude, but are not limited to mouth cleaning strips, toothpaste,toothbrushes, mouthwashes/dental rinses, denture care, mouth freshenersat-home teeth whiteners, dentifrices, and dental floss.

In at least one aspect, the disclosure provides formulations comprisingone or more compounds of the first aspect (of any of the embodiments setforth above, or as any individual compounds of Tables 2-9, orcombinations thereof) and one or more bitter compounds. The bittercompounds can come from any variety of sources. In some instances, thebitter compounds are components of certain natural products, such ascaffeine, quinine, green tea, catechins, polyphenols, green robustacoffee extract, green coffee extract, menthol and other mint compounds,and the like. Thus, in some embodiments, the composition is a beverageproduct, such as a tea or coffee product that includes one or morecompounds of the first aspect to reduce the bitter taste of suchcompounds in the beverage.

In some other embodiments, bitterness can arise from including certainproteins, such as protein isolates, into food products. Plant proteinisolates can be especially bitter in some instances. Thus, in someembodiments, the compositions disclosed herein include one or morecompounds of the first aspect and proteins, such as protein isolates.

In some embodiments, the protein isolates are made from animal products,such as whey or casein. In other embodiments, the protein isolates aremade from plant products like soy, hemp, chia seeds, rice, quinoa,beans, and the like. In some other embodiments, the protein is an algalprotein, such as spirulina. In such cases, the compounds of the firstaspect can block the bitter taste inherent to the protein, but can alsoblock some of the astringency of the “fishy” or amine taste in the algalprotein. In some other embodiments, the protein is a mycoprotein.

The compositions containing any of the foregoing proteins can be usefulfor making a variety of products. Non-limiting examples include proteinmixes, energy bars, protein-based chips or cookies, cheese-replacementproducts, meat-replacement products (such as vegan chicken, vegan beef,etc.). Some such products may also include synthetic heme-basedadditives to simulate the taste of blood in red meat. One or morecompounds of the first aspect are added to such products to offset thebitter taste of such heme-based additives.

In some other embodiments, bitterness can arise from compounds used totake the place of salt or monosodium glutamate (MSG). In many suchinstances, potassium chloride (KCl) is used. But KCl can impart a bittertaste. Thus, in some embodiments, the composition includes potassiumchloride (KCl) in combination with one or more compounds of the firstaspect.

In some embodiments, compounds as disclosed and described herein,individually or in combination may be included in food or beverageproducts or formulations. Examples of food and beverage products orformulations include, but are not limited to sweet coatings, frostings,or glazes for ingestible products or any entity included in the Soupcategory, the Dried Processed Food category, the Beverage category, theReady Meal category, the Canned or Preserved Food category, the FrozenProcessed Food category, the Chilled Processed Food category, the SnackFood category, the Baked Goods category, the Confectionery category, theDairy Product category, the Ice Cream category, the Meal Replacementcategory, the Pasta and Noodle category, and the Sauces, Dressings,Condiments category, the Baby Food category, and/or the Spreadscategory.

In general, the Soup category refers to canned/preserved, dehydrated,instant, chilled, UHT and frozen soup. For the purpose of thisdefinition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consommé) to sauces (cream or cheese-based soups).

The Dehydrated and Culinary Food Category usually means: (i) Cooking aidproducts such as: powders, granules, pastes, concentrated liquidproducts, including concentrated bouillon, bouillon and bouillon likeproducts in pressed cubes, tablets or powder or granulated form, whichare sold separately as a finished product or as an ingredient within aproduct, sauces and recipe mixes (regardless of technology); (ii) Mealsolutions products such as: dehydrated and freeze dried soups, includingdehydrated soup mixes, dehydrated instant soups, dehydratedready-to-cook soups, dehydrated or ambient preparations of ready-madedishes, meals and single serve entrees including pasta, potato and ricedishes; and (iii) Meal embellishment products such as: condiments,marinades, salad dressings, salad toppings, dips, breading, battermixes, shelf stable spreads, barbecue sauces, liquid recipe mixes,concentrates, sauces or sauce mixes, including recipe mixes for salad,sold as a finished product or as an ingredient within a product, whetherdehydrated, liquid or frozen.

The Beverage category usually means beverages, beverage mixes andconcentrates, including but not limited to, carbonated andnon-carbonated beverages, alcoholic and non-alcoholic beverages, readyto drink beverages, liquid concentrate formulations for preparingbeverages such as sodas, and dry powdered beverage precursor mixes. TheBeverage category also includes the alcoholic drinks, the soft drinks,sports drinks, isotonic beverages, and hot drinks. The alcoholic drinksinclude, but are not limited to beer, cider/perry, FABs, wine, andspirits. The soft drinks include, but are not limited to carbonates,such as colas and non-cola carbonates; fruit juice, such as juice,nectars, juice drinks and fruit flavored drinks; bottled water, whichincludes sparkling water, spring water and purified/table water;functional drinks, which can be carbonated or still and include sport,energy or elixir drinks; concentrates, such as liquid and powderconcentrates in ready to drink measure. The drinks, either hot or cold,include, but are not limited to coffee or ice coffee, such as fresh,instant, and combined coffee; tea or ice tea, such as black, green,white, oolong, and flavored tea; and other drinks including flavor-,malt- or plant-based powders, granules, blocks or tablets mixed withmilk or water.

The Snack Food category generally refers to any food that can be a lightinformal meal including, but not limited to Sweet and savory snacks andsnack bars. Examples of snack food include, but are not limited to fruitsnacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn,pretzels, nuts and other sweet and savory snacks. Examples of snack barsinclude, but are not limited to granola/muesli bars, breakfast bars,energy bars, fruit bars and other snack bars.

The Baked Goods category generally refers to any edible product theprocess of preparing which involves exposure to heat or excessivesunlight. Examples of baked goods include, but are not limited to bread,buns, cookies, muffins, cereal, toaster pastries, pastries, waffles,tortillas, biscuits, pies, bagels, tarts, quiches, cake, any bakedfoods, and any combination thereof.

The Ice Cream category generally refers to frozen dessert containingcream and sugar and flavoring. Examples of ice cream include, but arenot limited to: impulse ice cream; take-home ice cream; frozen yoghurtand artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean),and rice-based ice creams.

The Confectionery category generally refers to edible product that issweet to the taste. Examples of confectionery include, but are notlimited to candies, gelatins, chocolate confectionery, sugarconfectionery, gum, and the likes and any combination products.

The Meal Replacement category generally refers to any food intended toreplace the normal meals, particularly for people having health orfitness concerns. Examples of meal replacement include, but are notlimited to slimming products and convalescence products.

The Ready Meal category generally refers to any food that can be servedas meal without extensive preparation or processing. The ready mealincludes products that have had recipe “skills” added to them by themanufacturer, resulting in a high degree of readiness, completion andconvenience. Examples of ready meal include, but are not limited tocanned/preserved, frozen, dried, chilled ready meals; dinner mixes;frozen pizza; chilled pizza; and prepared salads.

The Pasta and Noodle category includes any pastas and/or noodlesincluding, but not limited to canned, dried and chilled/fresh pasta; andplain, instant, chilled, frozen and snack noodles.

The Canned/Preserved Food category includes, but is not limited tocanned/preserved meat and meat products, fish/seafood, vegetables,tomatoes, beans, fruit, ready meals, soup, pasta, and othercanned/preserved foods.

The Frozen Processed Food category includes, but is not limited tofrozen processed red meat, processed poultry, processed fish/seafood,processed vegetables, meat substitutes, processed potatoes, bakeryproducts, desserts, ready meals, pizza, soup, noodles, and other frozenfood.

The Dried Processed Food category includes, but is not limited to rice,dessert mixes, dried ready meals, dehydrated soup, instant soup, driedpasta, plain noodles, and instant noodles. The Chill Processed Foodcategory includes, but is not limited to chilled processed meats,processed fish/seafood products, lunch kits, fresh cut fruits, readymeals, pizza, prepared salads, soup, fresh pasta and noodles.

The Sauces, Dressings and Condiments category includes, but is notlimited to tomato pastes and purees, bouillon/stock cubes, herbs andspices, monosodium glutamate (MSG), table sauces, soy based sauces,pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup,mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickledproducts, and other sauces, dressings and condiments.

The Baby Food category includes, but is not limited to milk- orsoybean-based formula; and prepared, dried and other baby food.

The Spreads category includes, but is not limited to jams and preserves,honey, chocolate spreads, nut based spreads, and yeast based spreads.

The Dairy Product category generally refers to edible product producedfrom mammal's milk. Examples of dairy product include, but are notlimited to drinking milk products, cheese, yoghurt and sour milk drinks,and other dairy products.

Additional examples for ingestible compositions, particularly food andbeverage products or formulations, are provided as follows. Illustrativeingestible compositions include one or more confectioneries, chocolateconfectionery, tablets, countlines, bagged selflines/softlines, boxedassortments, standard boxed assortments, twist wrapped miniatures,seasonal chocolate, chocolate with toys, alfaj ores, other chocolateconfectionery, mints, standard mints, power mints, boiled sweets,pastilles, gums, jellies and chews, toffees, caramels and nougat,medicated confectionery, lollipops, liquorice, other sugarconfectionery, bread, packaged/industrial bread, unpackaged/artisanalbread, pastries, cakes, packaged/industrial cakes, unpackaged/artisanalcakes, cookies, chocolate coated biscuits, sandwich biscuits, filledbiscuits, savory biscuits and crackers, bread substitutes, breakfastcereals, rte cereals, family breakfast cereals, flakes, muesli, othercereals, children's breakfast cereals, hot cereals, ice cream, impulseice cream, single portion dairy ice cream, single portion water icecream, multi-pack dairy ice cream, multi-pack water ice cream, take-homeice cream, take-home dairy ice cream, ice cream desserts, bulk icecream, take-home water ice cream, frozen yoghurt, artisanal ice cream,dairy products, milk, fresh/pasteurized milk, full fat fresh/pasteurizedmilk, semi skimmed fresh/pasteurized milk, long-life/uht milk, full fatlong life/uht milk, semi skimmed long life/uht milk, fat-free longlife/uht milk, goat milk, condensed/evaporated milk, plaincondensed/evaporated milk, flavored, functional and other condensedmilk, flavored milk drinks, dairy only flavored milk drinks, flavoredmilk drinks with fruit juice, soy milk, sour milk drinks, fermenteddairy drinks, coffee whiteners, powder milk, flavored powder milkdrinks, cream, cheese, processed cheese, spreadable processed cheese,unspreadable processed cheese, unprocessed cheese, spreadableunprocessed cheese, hard cheese, packaged hard cheese, unpackaged hardcheese, yoghurt, plain/natural yoghurt, flavored yoghurt, fruitedyoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt,probiotic drinking yoghurt, chilled and shelf-stable desserts,dairy-based desserts, soy-based desserts, chilled snacks, fromage fraisand quark, plain fromage frais and quark, flavored fromage frais andquark, savory fromage frais and quark, sweet and savory snacks, fruitsnacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn,pretzels, nuts, other sweet and savory snacks, snack bars, granola bars,breakfast bars, energy bars, fruit bars, other snack bars, mealreplacement products, slimming products, convalescence drinks, readymeals, canned ready meals, frozen ready meals, dried ready meals,chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup,canned soup, dehydrated soup, instant soup, chilled soup, hot soup,frozen soup, pasta, canned pasta, dried pasta, chilled/fresh pasta,noodles, plain noodles, instant noodles, cups/bowl instant noodles,pouch instant noodles, chilled noodles, snack noodles, canned food,canned meat and meat products, canned fish/seafood, canned vegetables,canned tomatoes, canned beans, canned fruit, canned ready meals, cannedsoup, canned pasta, other canned foods, frozen food, frozen processedred meat, frozen processed poultry, frozen processed fish/seafood,frozen processed vegetables, frozen meat substitutes, frozen potatoes,oven baked potato chips, other oven baked potato products, non-ovenfrozen potatoes, frozen bakery products, frozen desserts, frozen readymeals, frozen pizza, frozen soup, frozen noodles, other frozen food,dried food, dessert mixes, dried ready meals, dehydrated soup, instantsoup, dried pasta, plain noodles, instant noodles, cups/bowl instantnoodles, pouch instant noodles, chilled food, chilled processed meats,chilled fish/seafood products, chilled processed fish, chilled coatedfish, chilled smoked fish, chilled lunch kit, chilled ready meals,chilled pizza, chilled soup, chilled/fresh pasta, chilled noodles, oilsand fats, olive oil, vegetable and seed oil, cooking fats, butter,margarine, spreadable oils and fats, functional spreadable oils andfats, sauces, dressings and condiments, tomato pastes and purees,bouillon/stock cubes, stock cubes, gravy granules, liquid stocks andfonds, herbs and spices, fermented sauces, soy based sauces, pastasauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise,regular mayonnaise, mustard, salad dressings, regular salad dressings,low fat salad dressings, vinaigrettes, dips, pickled products, othersauces, dressings and condiments, baby food, milk formula, standard milkformula, follow-on milk formula, toddler milk formula, hypoallergenicmilk formula, prepared baby food, dried baby food, other baby food,spreads, jams and preserves, honey, chocolate spreads, nut-basedspreads, and yeast-based spreads. Exemplary ingestible compositions alsoinclude confectioneries, bakery products, ice creams, dairy products,sweet and savory snacks, snack bars, meal replacement products, readymeals, soups, pastas, noodles, canned foods, frozen foods, dried foods,chilled foods, oils and fats, baby foods, or spreads or a mixturethereof. Exemplary ingestible compositions also include breakfastcereals, sweet beverages or solid or liquid concentrate compositions forpreparing beverages, ideally so as to enable the reduction inconcentration of previously known saccharide sweeteners, or artificialsweeteners.

Some embodiments provide a chewable composition that may or may not beintended to be swallowed. In some embodiments, the chewable compositionmay be gum, chewing gum, sugarized gum, sugar-free gum, functional gum,bubble gum including compounds as disclosed and described herein,individually or in combination.

Typically at least a sweet receptor modulating amount, a sweet receptorligand modulating amount, a sweet flavor modulating amount, a sweetflavoring agent amount, a sweet flavor enhancing amount, or atherapeutically effective amount of one or more of the present compoundswill be added to the ingestible composition, optionally in the presenceof sweeteners so that the sweet flavor modified ingestible compositionhas an increased sweet taste as compared to the ingestible compositionprepared without the compounds of the present invention, as judged byhuman beings or animals in general, or in the case of formulationstesting, as judged by a majority of a panel of at least eight humantaste testers, via procedures commonly known in the field.

In some embodiments, compounds as disclosed and described herein,individually or in combination, modulate the sweet taste or other tasteproperties of other natural or synthetic sweet tastants, and ingestiblecompositions made therefrom. In one embodiment, the compounds asdisclosed and described herein, individually or in combination, may beused or provided in its ligand enhancing concentration(s). For example,the compounds as disclosed and described herein, individually or incombination, may be present in an amount of from about 0.001 ppm to 100ppm, or narrower alternative ranges from about 0.1 ppm to about 10 ppm,from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 10ppm, from about 0.01 ppm to about 5 ppm, or from about 0.02 ppm to about2 ppm, or from about 0.01 ppm to about 1 ppm.

Some embodiments provide a sweet enhancing composition. The sweetenhancing composition comprises a compound of the present invention in asweet flavor enhancing amount in combination with a first amount ofsweetener, wherein the sweetening is more than the sweetening providedby the first amount of sweetener without the compound. In someembodiments, the sweetener may be common saccharide sweeteners, e.g.,sucrose, fructose, glucose, and sweetener compositions comprisingnatural sugars, such as corn syrup (including high fructose corn syrup)or other syrups or sweetener concentrates derived from natural fruit andvegetable sources; rare natural sugars including D-allose, D-psicose,L-ribose, D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose, andD-leucrose; semi-synthetic “sugar alcohol” sweeteners such aserythritol, isomalt, lactitol, mannitol, sorbitol, xylitol,maltodextrin, and the like; and artificial sweeteners such as aspartame,saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In someembodiments, the sweetener may be selected from the group consisting ofcyclamic acid, mogroside, tagatose, maltose, galactose, mannose,sucrose, fructose, lactose, neotame and other aspartame derivatives,glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt,hydrogenated glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH),stevioside, rebaudioside A and other sweet Stevia-based glycosides,carrelame and other guanidine-based sweeteners. In some embodiments, thesweetener may combinations of two or more sweeteners as disclosedherein. In some embodiments, the sweetener may combinations of two,three, four or five sweeteners as disclosed herein. In some embodiments,the sweetener may be a sugar. In some embodiments, the sweetener may bea combination of one or more sugars and other natural and artificialsweeteners. In some embodiments, the sweetener may be a sugar. In someembodiments, the sugar is cane sugar. In some embodiments, the sugar isbeet sugar. In some embodiments, the sweetener may be a combination ofone or more sugars and other natural and artificial sweeteners. In someembodiments, the sugar may be sucrose, fructose, glucose or combinationsthereof (for example, high fructose corn syrup). In some embodiments,the sugar may be sucrose. In some embodiments, the sugar may be acombination of fructose and glucose. In some embodiments, the sugar maybe a combination of about 55% fructose and about 42% glucose. In someembodiments, the sugar may be a combination of about 42% fructose andabout 53% glucose. In some embodiments, the sugar may be a combinationof about 90% fructose and about 10% glucose. In some embodiments, thesweetener may be a rare sugar. In some embodiments, the rare sugar isselected from the group consisting of D-allose, D-psicose, L-ribose,D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose, D-leucrose andcombinations thereof. In some embodiments, the rare sugar is D-psicose.In some embodiments, the rare sugar is D-tagatose. In some embodiments,the sweetener is an artificial sweetener. In some embodiments, theartificial sweetener may be sucralose.

In some embodiments, compounds as disclosed and described herein,individually or in combination, provide enhancement of potency of asweetener at the T1R2/T1R3 taste receptor as measured by an enhancementratio, defined as the ratio of EC₅₀ of the sweetener with and withoutthe compound described herein. In some embodiments, compounds asdisclosed and described herein, individually or in combination, provideenhancement ratio of greater than 1 and less than 10. In someembodiments, compounds as disclosed and described herein, individuallyor in combination, provide an enhancement ratio from 10 to 20. In someembodiments, compounds as disclosed and described herein, individuallyor in combination, provide an enhancement ratio greater than 20. In someembodiments, the sweetener may be common saccharide sweeteners, e.g.,sucrose, fructose, glucose, and sweetener compositions comprisingnatural sugars, such as corn syrup (including high fructose corn syrup)or other syrups or sweetener concentrates derived from natural fruit andvegetable sources; rare natural sugars including D-allose, D-psicose,L-ribose, D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose, andD-leucrose; semi-synthetic “sugar alcohol” sweeteners such aserythritol, isomalt, lactitol, mannitol, sorbitol, xylitol,maltodextrin, and the like; and artificial sweeteners such as aspartame,saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In someembodiments, the sweetener may be selected from the group consisting ofcyclamic acid, mogroside, tagatose, maltose, galactose, mannose,sucrose, fructose, lactose, neotame and other aspartame derivatives,glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt,hydrogenated glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH),stevioside, rebaudioside A and other sweet Stevia-based glycosides,carrelame and other guanidine-based sweeteners. In some embodiments, thesweetener may combinations of two or more sweeteners as disclosedherein. In some embodiments, the sweetener may combinations of two,three, four or five sweeteners as disclosed herein. In some embodiments,the sweetener may be a sugar. In some embodiments, the sweetener may bea combination of one or more sugars and other natural and artificialsweeteners. In some embodiments, the sweetener may be a sugar. In someembodiments, the sweetener may be a combination of one or more sugarsand other natural and artificial sweeteners. In some embodiments, thesugar may be sucrose, fructose, glucose or combinations thereof (forexample, high fructose corn syrup). In some embodiments, the sugar maybe sucrose. In some embodiments, the sugar may be a combination offructose and glucose. In some embodiments, the sugar may be acombination of about 55% fructose and about 42% glucose. In someembodiments, the sugar may be a combination of about 42% fructose andabout 53% glucose. In some embodiments, the sugar may be a combinationof about 90% fructose and about 10% glucose. In some embodiments, thesweetener may be a rare sugar. In some embodiments, the rare sugar isselected from the group consisting of D-allose, D-psicose, L-ribose,D-tagatose, L-glucose, L-fucose, L-arbinose, D-turanose, D-leucrose andcombinations thereof. In some embodiments, the rare sugar is D-psicose.In some embodiments, the rare sugar is D-tagatose. In some embodiments,the sweetener is an artificial sweetener. In some embodiments, theartificial sweetener may be sucralose.

In some embodiments, compounds as disclosed and described herein,individually or in combination, may be provided in a flavoringconcentrate formulation, e.g., suitable for subsequent processing toproduce a ready-to-use (i.e., ready-to-serve) product. By “a flavoringconcentrate formulation”, it is meant a formulation which should bereconstituted with one or more diluting medium to become a ready-to-usecomposition. The term “ready-to-use composition” is used hereininterchangeably with “ingestible composition”, which denotes anysubstance that, either alone or together with another substance, can betaken by mouth whether intended for consumption or not. In oneembodiment, the ready-to-use composition includes a composition that canbe directly consumed by a human or animal. The flavoring concentrateformulation is typically used by mixing with or diluted by one or morediluting medium, e.g., any consumable or ingestible ingredient orproduct, to impart or modify one or more flavors to the diluting medium.Such a use process is often referred to as reconstitution. Thereconstitution can be conducted in a household setting or an industrialsetting. For example, a frozen fruit juice concentrate can bereconstituted with water or other aqueous medium by a consumer in akitchen to obtain the ready-to-use fruit juice beverage. In anotherexample, a soft drink syrup concentrate can be reconstituted with wateror other aqueous medium by a manufacturer in large industrial scales toproduce the ready-to-use soft drinks. Since the flavoring concentrateformulation has the flavoring agent or flavor modifying agent in aconcentration higher than the ready-to-use composition, the flavoringconcentrate formulation is typically not suitable for being consumeddirectly without reconstitution. There are many benefits of using andproducing a flavoring concentrate formulation. For example, one benefitis the reduction in weight and volume for transportation as theflavoring concentrate formulation can be reconstituted at the time ofusage by the addition of suitable solvent, solid or liquid.

In one embodiment, the flavoring concentrate formulation comprises i)compounds as disclosed and described herein, individually or incombination; ii) a carrier; and iii) optionally at least one adjuvant.The term “carrier” denotes a usually inactive accessory substance, suchas solvents, binders, or other inert medium, which is used incombination with the present compound and one or more optional adjuvantsto form the formulation. For example, water or starch can be a carrierfor a flavoring concentrate formulation. In some embodiments, thecarrier is the same as the diluting medium for reconstituting theflavoring concentrate formulation; and in other embodiments, the carrieris different from the diluting medium. The term “carrier” as used hereinincludes, but is not limited to, ingestibly acceptable carrier.

The term “adjuvant” denotes an additive which supplements, stabilizes,maintains, or enhances the intended function or effectiveness of theactive ingredient, such as the compound of the present invention. In oneembodiment, the at least one adjuvant comprises one or more flavoringagents. The flavoring agent may be of any flavor known to one skilled inthe art or consumers, such as the flavor of chocolate, coffee, tea,mocha, French vanilla, peanut butter, chai, or combinations thereof. Inanother embodiment, the at least one adjuvant comprises one or moresweeteners. The one or more sweeteners can be any of the sweetenersdescribed in this application. In another embodiment, the at least oneadjuvant comprises one or more ingredients selected from the groupconsisting of a emulsifier, a stabilizer, an antimicrobial preservative,an antioxidant, vitamins, minerals, fats, starches, protein concentratesand isolates, salts, and combinations thereof. Examples of emulsifiers,stabilizers, antimicrobial preservatives, antioxidants, vitamins,minerals, fats, starches, protein concentrates and isolates, and saltsare described in U.S. Pat. No. 6,468,576, the content of which is herebyincorporated by reference in its entirety for all purposes.

In one embodiment, the present flavoring concentrate formulation can bein a form selected from the group consisting of liquid includingsolution and suspension, solid, foamy material, paste, gel, cream, and acombination thereof, such as a liquid containing certain amount of solidcontents. In one embodiment, the flavoring concentrate formulation is inform of a liquid including aqueous-based and nonaqueous-based. In someembodiments, the present flavoring concentrate formulation can becarbonated or non-carbonated.

The flavoring concentrate formulation may further comprise a freezingpoint depressant, nucleating agent, or both as the at least oneadjuvant. The freezing point depressant is an ingestibly acceptablecompound or agent which can depress the freezing point of a liquid orsolvent to which the compound or agent is added. That is, a liquid orsolution containing the freezing point depressant has a lower freezingpoint than the liquid or solvent without the freezing point depressant.In addition to depress the onset freezing point, the freezing pointdepressant may also lower the water activity of the flavoringconcentrate formulation. The examples of the freezing point depressantinclude, but are not limited to, carbohydrates, oils, ethyl alcohol,polyol, e.g., glycerol, and combinations thereof. The nucleating agentdenotes an ingestibly acceptable compound or agent which is able tofacilitate nucleation. The presence of nucleating agent in the flavoringconcentrate formulation can improve the mouthfeel of the frozen Blushesof a frozen slush and to help maintain the physical properties andperformance of the slush at freezing temperatures by increasing thenumber of desirable ice crystallization centers. Examples of nucleatingagents include, but are not limited to, calcium silicate, calciumcarbonate, titanium dioxide, and combinations thereof.

In one embodiment, the flavoring concentrate formulation is formulatedto have a low water activity for extended shelf life. Water activity isthe ratio of the vapor pressure of water in a formulation to the vaporpressure of pure water at the same temperature. In one embodiment, theflavoring concentrate formulation has a water activity of less thanabout 0.85. In another embodiment, the flavoring concentrate formulationhas a water activity of less than about 0.80. In another embodiment, theflavoring concentrate formulation has a water activity of less thanabout 0.75.

In one embodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 2 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 5 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 10 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 15 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 20 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 30 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 40 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 50 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 60 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is up to 100 times of the concentrationof the compound in a ready-to-use composition.

In some embodiments, the disclosure provides pharmaceutical compositionscomprising one or more compounds of the first aspect and one or morebitter compounds. In some embodiments, the bitter compounds arepharmaceutical APIs, such as antibiotics. Children often have muchgreater sensitivity to bitter tastes than adults, so the use ofbitterness blockers can be especially useful in pharmaceuticalcompositions for pediatric administration.

In one embodiment, when administered to a patient, the compounds asdisclosed and described herein and the optional pharmaceuticallyacceptable vehicles are sterile. In one embodiment, water is a preferredvehicle when a compound as disclosed and described herein isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present pharmaceutical compositions, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents may be used. In someinstances, the pharmaceutical compositions are liquid solutions orsuspensions, that include, among other things, flavorants, pHmodulators, natural or artificial sweeteners, and the like.

Pharmaceutical compositions comprising a compound as disclosed anddescribed herein may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the presentinvention into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.

In some embodiments, the pharmaceutical compositions can take the formof solutions, suspensions, emulsion, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule.

For topical administration a compound as disclosed and described hereinmay be formulated as solutions, gels, ointments, creams, suspensions,etc. as is well-known in the art.

In some embodiments, compounds as disclosed and described herein may beformulated in accordance with routine procedures as a pharmaceuticalcomposition adapted for intravenous administration to human beings.Typically, compounds for intravenous administration are solutions insterile isotonic aqueous buffer. For injection, a compound may beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks' solution, Ringer's solution, orphysiological saline buffer. The solution may contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Whennecessary, the pharmaceutical compositions may also include asolubilizing agent.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered pharmaceutical compositions may contain one or moreoptionally agents, for example, sweetening agents such as fructose,aspartame or saccharin; flavoring agents such as peppermint, oil ofwintergreen, or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation.

Moreover, where in tablet or pill form, the pharmaceutical compositionsmay be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compounds of the present invention. In these laterplatforms, fluid from the environment surrounding the capsule is imbibedby the driving compound, which swells to displace the agent or agentcomposition through an aperture. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations. A time delay material suchas glycerol monostearate or glycerol stearate may also be used. Oralcompositions can include standard vehicles such as mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate, etc. Such vehicles are preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the present invention with a pharmaceutically acceptable vehicle.Preferably, the pharmaceutically acceptable vehicle is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of compounds of the invention. Preferably, thismaterial is liquid such as an alcohol, glycol, polyglycol or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart.

A compound as disclosed and described herein, and/or pharmaceuticalcomposition thereof, will generally be used in an amount effective toachieve the intended purpose, i.e., bitterness masking. In general, theeffective amount is an amount ranging from 5 to 2000 ppm, or from 5 to1000 ppm, or from 5 to 800 ppm, or from 5 to 500 ppm, or from 5 to 400ppm, or from 5 to 300 ppm, or from 5 to 200 ppm, based on the totalweight of the composition.

Yet another embodiment of the invention generally pertains to a methodof blocking bitterness by using any of the compositions discussedherein.

In illustrative embodiments compounds according to the invention will beused to block/reduce/modify bitter taste associated with compounds thatactivate the hT2R54 receptor and/or which further activate the hT2R⁶¹,hT2R⁶⁴ and/or hT2R⁷⁵ taste receptors.

In specific exemplary embodiments compounds according to the inventionwill be used to block/reduce/modify bitter taste associated withcompounds that activate the hT2R54 receptor and/or the hT2R⁶¹, hT2R⁶⁴and/or hT2R⁷⁵ taste receptors such as acetaminophen, dextromethorphan,dequaliunium, chloroquine, and guaifenesin and their salts, hydrates,solvates or prodrug forms thereof.

Additionally the compounds of the present invention may be used inassociation with other bitter taste blocker compounds such as are setforth in the following table.

TABLE 1

In some embodiments, the compositions for modifying bitter tasteperception may additionally comprise one or more compounds described inPCT Publication No. WO 2014/130582, which is incorporated herein byreference in its entirety. In some embodiments, the compositionsdisclosed above may be used in combination with a cooling agent. Suchcooling agents useful for combination with the compounds disclosedherein are known in the art, and include those described in U.S.2013/0324557, WO 2014/130582, U.S. Pat. No. 7,923,585, U.S.2008/0319055, U.S. Pat. No. 7,893,110, U.S. 2009/0105237, U.S.2009/0098066, U.S. 2010/0035938, U.S. Pat. Nos. 8,263,046, 7,959,958,U.S. 2008/0300314, U.S. 2009/0312384, U.S. Pat. Nos. 8,309,598,7,935,848, U.S. 2010/0297038, U.S. Pat. Nos. 8,377,422, 8,664,261, U.S.2011/0091531, U.S. 2013/0323388, U.S. 2014/0341821, U.S. 2010/0086498,U.S. 2014/0186272, U.S. Pat. No. 6,884,906, U.S. 2011/0070329, U.S. Pat.Nos. 8,575,349, 5,725,865, 5,843,466, WO 2011/147455, U.S. Pat. No.8,007,771, WO 2004/037764, U.S. Pat. No. 6,627,233, WO 2011/159935, U.S.Pat. Nos. 7,767,243, 7,662,576, 5,372,824, 5,009,893, 5,698,181,7,189,760, 7,030,273, WO 02/091849, U.S. Pat. Nos. 5,286,500, 3,488,419,6,515,188, 6,407,293, 4,459,425, 3,419,543, U.S. 2006/0210482, U.S. Pat.Nos. 6,328,982, 7,025,999, EP 1332772, U.S. Pat. No. 4,157,384, WO2014/090293, U.S. 2008/0175800, U.S. Pat. Nos. 8,344,025, 8,927,605,U.S. 2011/0305657, U.S. 2013/0202543, and U.S. 2014/0335224, which areincorporated by reference herein in their entireties.

In certain embodiments the composition blocks bitterness associated withAcetaminophen, Dextromethorphan, Dequalinium, Chloroquine, and/orGuaifenesin, which activate T2R54 alone or T2R54 and other receptors.

In some embodiments, the composition comprises one or a combination oftwo or more of the compounds and compositions disclosed herein, may befurther combined with one or more acids or sour flavorants.Representative sour flavorants include but are not limited to: ascorbicacid, benzoic acid, gallic acid, glucuronic acid, adipic acid, glutaricacid, malonic acid, succinic acid, malic acid, acetic acid, lactic acid,citric acid, tartaric acid, fumaric acid, phosphoric acid,pyrophosphoric acid, tannic acid, vinegar, lemon juice, lime juice,acidic fruit juices, and acidic fruit extracts.

In some embodiments, the composition comprises one or a combination oftwo or more of the compounds and compositions disclosed herein, may befurther combined with one or more salts or salt flavor enhancers.Representative salts or salt flavor enhancers include but are notlimited to: mineral salts, sodium chloride, potassium chloride,magnesium chloride, ammonium chloride, sodium gluconate, sodiumphosphates, glycine, L-alanine, L-valine, L-leucine, L-isoleucine,L-phenylalanine, L-tyrosine, L-glutamine, L-glutamic acid, L-asparagine,L-aspartic acid, L-serine, L-threonine, L-cysteine, L-methionine,L-proline, L-lysine, L-arginine, L-tryptophan, L-histidine,L-pyrolysine, L-pyroglutamine, L-4-trans-hydroxyproline,L-3-cis-hydroxyproline, L-homoserine, L-homocysteine, L-cystine,L-ornithine and L-citrulline, L-glutamine, L-glutamic acid,L-asparagine, L-aspartic acid, L-valine, L-arginine and L-lysine.

In some embodiments, the composition comprises one or a combination oftwo or more of the compounds and compositions disclosed herein, whichmay be further combined with one or more umami flavor compounds or umamiflavor enhancing compounds. Representative umami flavor compounds orumami flavor enhancing compounds include but are not limited to thecompounds identified in U.S. Patent Application Publications2005/0084506A1, U.S. 2009/0111834A1, U.S. 2012/0201763A1, U.S.2015/0093339A1, U.S. 2006/0263411A1, U.S. 2012/0226047A1, and2009/0220662A1. Additional representative umami flavor compounds orumami flavor enhancing compounds include but are not limited to:hydrolyzed soy protein, hydrolyzed corn protein, hydrolyzed wheatprotein, anchovy, anchovy paste, fish sauce, yeast extract, nutritionalyeast, hydrolyzed yeast extract, mushrooms, mushroom powder, dehydratedmushrooms, mushroom extract, kombucha, hydrolyzed vegetable protein,oyster sauce, soy sauce, soy extract, tamari, miso powder, miso paste,parmesan cheese, parmesan cheese solids, kombu powder, kombu, dehydratedkombu, kombu paste, non, nori powder, non paste, seaweed, dehydratedseaweed, seaweed powder, seaweed extract, tomato, dehydrated tomato,tomato powder, tomato extract, vegetable powder, vegetable extract, wheypowder, whey solids, whey, collagen, gelatin, textured vegetableprotein, sodium caseinate, calcium caseinate, magnesium caseinate,potassium caseinate, glyoxylic acid, 3-methyl-2-oxo-butanoic acid,3-methyl-2-oxo-pentanoic acid, 4-methyl-2-oxo-pentanoic acid,3-hydroxy-2-oxo-propanoic acid, oxalacetic acid, 2-oxo-glutaric acid,2-oxo-3-phenyl-propanoic acid, 3-(4-hydroxyphenyl)-2-oxo-propanoic acid,2-oxo-1H-indole-3-propanoic acid, 2-oxo-1H-imidazole-4-propanoic acid,4-methylthio-2-oxo-butanoic acid, 3-mercapto-2-oxo-propanoic acid,3-hydroxy-2-oxo-butanoic acid, 6-amino-2-oxo-hexanoic and5-guanidino-2-oxo-pentanoic acid, 2-amino-butanoic acid, α-alanine,glycine, norvaline, valine, aspartic acid, norleucine, leucine,isoleucine, serine, threonine, glutamic acid, phenylalanine, tyrosine,cysteine, methionine, lysine, tryptophane, histidine, arginine,asparagine, glutamine, cystine, citrulline, theanine,γ-methylene-glutamic acid, isoeugenol, 2-propylphenol, p-vinylguaiacol,2-acetylpyrazine, 2-ethyl-3,5-dimethylpyrazine, 2,3,5-trimethylpyrazine,2,3-diethyl-5-methylpyrazine, 3-ethyl-2-methylpyrazine, dimethylsulfide, dimethyl disulfide, dimethyl trisulfide, methylpropyldisulfide, 2-methylthiophenol, methional (3-methylthiopropanal),2-octenal, 2,4-nonadienal, 2,4-decadienal, 2,4-undecadienal,2-methoxybenzaldchyde, 2,4-dodecadienal, decenal, methyl2-furanecarboxylate, 2-ethyl-4-hydroxy-3-methyl 5(2H)-furanone,2,6-dimethylbenzenethiol 2-nonen-1-ol, 10-undecenoic acid, undecanoicacid, isodecanoic acid and isononanoic acid, 2-oxo-butanoic acid,oxalacetic acid, 3-methyl-2-oxo-butanoic acid, 3-methyl-2-oxo-pentanoicacid, 2-oxo-glutaric and 3-mercapto-2-oxo-propanoic acid, NaCl, KCl,MSG, guanosine monophosphate (GMP), inosin monophospahte (IMP),ribonucleotides such as disodium inosinate, disodium guanylate,N-(2-hydroxyethyl)-lactamide, N-lactoyl-GMP, N-lactoyl tyramine, gammaamino butyric acid, allyl cysteine,1-(2-hydroxy-4-methoxylphenyl)-3-(pyridine-2-yl)propan-1-one, arginine,potassium chloride, ammonium chloride, succinic acid,N-(2-methoxy-4-methyl benzyl)-N′-(2-(pyridin-2-yl)ethyl) oxalamide,N-(heptan-4-yl)benzo(D)(1,3)dioxole-5-carboxamide,N-(2,4-dimethoxybenzyl)-N′-(2-(pyridin-2-yl)ethyl) oxalamide,N-(2-methoxy-4-methyl benzyl)-N′-2(2-(5-methyl pyridin-2-yl)ethyl)oxalamide, cyclopropyl-E,Z-2,6-nonadienamide, glutamic acid, glutamate,monosodium glutamate, monopotassium glutamate, monoammonium glutamate,calcium diglutamate, magnesium diglutamate, L-asparagine or a saltthereof, 5′-ribonucleotides or their salts, calcium 5′-ribonucleotides,disodium 5′-ribonucleotides, dipotassium 5′-ribonucleotides, inosinicacid, guanylic acid, adenosinic acid, inosinates, guanylates, andadenylates, guanosine 5′-monophosphate, inosine 5′-monophosphate,5′-adenylate, disodium guanylate, disodium inosinate, disodiumadenylate; dipotassium guanylate, dipotassium inosinate, dipotassiumadenylate, calcium guanylate, calcium inosinate, calcium adenylate,maltol, ethyl maltol, glycine, L-leucine, autolyzed or hydrolyzedproteins (e.g. autolyzed yeast, hydrolyzed yeast, hydrolyzed vegetableproteins), Koji-Aji (Ajinomoto Food Ingredients), fermented wheatgluten, Glutathione, Glutamyl Glutamic Acid, (Z)-6-Dodecen-4-olide,Inosinic acid, Dodec-Z6-en-4-olide, Glutamic Acid, L-Aconitic Acid,N-(1-deoxy-fructos-1-yl) glutamate, hydrolyzed vegetable protein, Methylalpha-D-Glucoside, 2,3-Di-lysine, Methyl alpha-D-Glucoside2,3-Di-ornithine, L-Asparagine, L-a-glutamyl-L-a-glutamyl-L-Glutamicacid, L-a-aspartyl-L-a-glutamyl-Glutamyl valine, Wheat glutenhydrolyzate, Aspartic acid L-,L-a-aspartyl-L-a-aspartyl-L-a-aspartyl-Docosahexaenoic acid, and(4Z,7Z,10Z,13Z,16Z,19Z)-L-Theanine, allyl cysteine, propenyl cysteine,S-α,β-dicarboxyethyl) γ-L-glutamyl-L-cysteinyl-glycine, S-(α,β-dicarboxyethyl) cysteine, 3-(carboxymethoxy)-alanine,S-carboxymethyl-glutathione (glutaramic acid),S-carboxymethyl-cysteinyl-glycine, (S-carboxymethyl)-lysyl-cysteine,S-dicarboxymethyl-glutathione, S-carboxymethyl-cysteine,S-(1,2-dicarboxyethyl)-glutathione, and S-(1,2-dicarboxyethyl)-cysteine,N-acetyl GMP, N-formyl GMP, N-propanoyl GMP, N-butanoyl GMP, N-pentanoylGMP, N-hexanoyl GMP, N-heptanoyl GMP, N-octanoyl GMP, N-oxalyl GMP,N-succinyl GMP, N-glutaryl GMP, N-fumaryl GMP, N-maleyl GMP, N-adipylGMP, N-citryl GMP, N-galloyl GMP, N-oxalacetyl-GMP, N-feruloyl GMP,N-pyruvyl GMP, N-benzoyl GMP, N-vanilloyl GMP, N-anthranoyl GMP,N-caffeoyl GMP, N-cinnamoyl GMP, N-acetyl AMP, N-formyl AMP, N-propanoylAMP, N-butanoyl AMP, N-pentanoyl AMP, N-hexanoyl AMP, N-heptanoyl AMP,N-octanoyl AMP, N-oxalyl AMP, N-succinyl AMP, N-glutaryl AMP, N-fumarylAMP, N-maleyl AMP, N-adipyl AMP, N-citryl AMP, N-galloyl AMP,N-oxalacetyl-AMP, N-feruloyl AMP, N-pyruvyl AMP, N-benzoyl AMP,N-vanilloyl AMP, N-anthranoyl AMP, N-caffeoyl AMP, N-cinnamoyl AMP,N-acetyl CMP, N-formyl CMP, N-propanoyl CMP, N-butanoyl CMP, N-pentanoylCMP, N-hexanoyl CMP, N-heptanoyl CMP, N-octanoyl CMP, N-oxalyl CMP,N-succinyl CMP, N-glutaryl CMP, N-fumaryl CMP, N-maleyl CMP, N-adipylCMP, N-citryl CMP, N-galloyl CMP, N-oxalacetyl-CMP, N-feruloyl CMP,N-pyruvyl CMP, N-benzoyl CMP, N-vanilloyl CMP, N-anthranoyl CMP,N-caffeoyl CMP, N-cinnamoyl CMP, N-acetyl GMP, N-formyl GMP, N-propanoylGMP, N-butanoyl GMP, N-pentanoyl GMP, N-hexanoyl GMP, N-heptanoyl GMP,N-octanoyl GMP, N-oxalyl GMP, N-succinyl GMP, N-glutaryl GMP, N-fumarylGMP, N-maleyl GMP, N-adipyl GMP, N-citryl GMP, N-galloyl GMP,N-oxalacetyl-GMP, N-feruloyl GMP, N-pyruvyl GMP, N-benzoyl GMP,N-vanilloyl GMP, N-anthranoyl GMP, N-caffeoyl GMP, N-cinnamoyl GMP,flavor modifiers created by maillard reactions, S-(α, β-dicarboxyethyl)γ-L-glutamyl-L-cysteinyl-glycine, S-(α, β-dicarboxyethyl) cysteine,3-(carboxymethoxy)-alanine, S-carboxymethyl-glutathione (glutaramicacid), S-carboxymethyl-cysteinyl-glycine,(S-carboxymethyl)-lysyl-cysteine, S-dicarboxymethyl-glutathione,S-carboxymethyl-cysteine, S-(1,2-dicarboxyethyl)-glutathione, andS-(1,2-dicarboxyethyl)-cysteine, Gamma-L-glutamyl-L-cysteinyl-glycine ory-Glu-Cys-Gly, Rubemamine, rubemamide, rubescenamine, Rubescenamide,zanthosine, zanthosinamide, dioxamide, dioxamine, zanthomamine, andzanthomamide.

Umami flavor compounds or umami flavor enhancing compounds may alsoinclude peptides set forth in Nakata et al., Biosci. Biotechnol.Biochem. (1995) 59(4):689-93.

In some embodiments, the compounds and compositions described herein,are incorporated, either alone or in combination with one or more of theadditional compounds described herein, into a smoking article or vaporinhalation (“e-cigarette”) device. Such articles and devices are wellknown in the art, including but not limited to, cigars, cigarettes,loose pipe tobacco, flavored cigars, flavored cigarettes, rollingpapers, pipes, water pipes, kretek cigarettes, bidis, mouthpieces (e.g.,of a hookah), and electronic cigarettes. In some embodiments, thecompounds and compositions described herein, which may be furthercombined with one or more cooling agents, may be applied directly to asmoking article at any time during or after the manufacture of thesmoking article. In some further embodiments, the compounds andcompositions described herein, may be provided as a liquid, solid, orconcentrate to be applied to a smoking article or vaporizer fluid. Insome further embodiments, the compounds and compositions describedherein, can be incorporated into a vaporizer fluid. In some embodimentsthe vaporizer fluid further comprises propylene glycol, water, nicotine,glycerin, and/or polyethylene glycol. In some embodiments, the smokingarticle comprises tobacco. In some embodiments, the smoking articlecomprises tobacco, cannabis, cloves, and/or tendu or tembumi leaves.

In some embodiments, the compounds and compositions described herein,are incorporated, either alone or in combination with one or more of theadditional compounds described herein, with cannabis or acannabis-related or cannabis-derived or cannabis-containing product.Such cannabis-related or cannabis-derived or cannabis-containingproducts include, but are not limited to: dried cannabis; undriedcannabis; cannabis-derived or cannabis-containing tinctures;cannabis-derived or cannabis-containing oils, e.g., hash oil;cannabis-derived topical preparations, e.g., ointments and balmscontaining or derived from cannabis; and concentrates, e.g, hash.Additionally, the compounds and compositions described herein, areincorporated, either alone or in combination with one or more of theadditional compounds described herein, with edible products includingbut not limited to any of the ingestible and/or edible productsdiscussed herein, e.g., foodstuffs and beverages, which may furthercontain cannabis or a cannabis-related or cannabis-derived products.

In some embodiments, the pharmaceutical composition disclosed herein maycontain a cannabis-derived compound, e.g., any cannabinoid,tetrahydrocannabinol, (−)-trans-Δ⁹-tetrahydrocannabinol, or otherisomers or related compounds derived from cannabis in addition tocontaining any of the compounds disclosed herein, which may further becombined with one or more cooling agents.

Methods of Preparation

The compounds disclosed herein may be synthesized by methods describedbelow, or by modification of these methods. Ways of modifying themethodology include, among others, temperature, solvent, reagents etc.,known to those skilled in the art. In general, during any of theprocesses for preparation of the compounds disclosed herein, it may benecessary or desirable to protect sensitive or reactive groups on any ofthe molecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and P. G.M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.)Wiley, New York (1999), which are both hereby incorporated herein byreference in their entirety. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art. Syntheticchemistry transformations useful in synthesizing applicable compoundsare known in the art and include e.g. those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers, 1989, or L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons, 1995, which are both hereby incorporated herein byreference in their entirety. The routes shown and described herein areillustrative only and are not intended, nor are they to be construed, tolimit the scope of the claims in any manner whatsoever. Those skilled inthe art will be able to recognize modifications of the disclosedsyntheses and to devise alternate routes based on the disclosuresherein; all such modifications and alternate routes are within the scopeof the claims.

Some exemplary synthetic methods for preparing the present compounds areillustrated in Scheme 1 below.

As depicted in Scheme 1, aniline building blocks I and activatedcarboxylic acids II and A-II can be allowed to react under various amidecoupling conditions to yield either III or A-III. The species II andA-II can be generated in situ but may also be either commerciallyavailable or easily accessible as storable intermediates. Compounds IIIcan be used either as final materials or as intermediates (R⁵=leavinggroup). Thus, if R⁵ is a leaving group (LG), III can be treated withamine building blocks of choice to form intermediates V. Subsequently,if substituent R⁷ of compound V is a protected amine group, V can besubmitted to conditions that allow for the removal of amine protectinggroups to yield intermediates VI. Likewise, amine protecting groups ofA-III can be removed under similar conditions to yield intermediatesA-IV. These amine intermediates (VI & A-IV) can in turn be allow toreact with various electrophiles under coupling, substitution, oraddition conditions to furnish VIII and A-V, respectively.

However, if the substituent R⁷ of intermediates V is an ester group, Vcan instead be submitted to saponification conditions to yield IX whichin turn can be submitted to amide coupling conditions to yield compoundsX. Alternatively, compounds VIII and X can also be prepared fromintermediates III and building blocks XI and XII, respectively. On theother hand, compound A-V can also be generated from anilines I and acidbuilding blocks A-VI. The latter building blocks (XI, XII, & A-VI) areeither commercially available or can be synthesized using methodssimilar to those described above or in the literature.

EXAMPLE 1 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(3-methylbutanoyl)piperazin-1-yl)acetamide(1)

To a suspension of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochlorides (Example 1a)(38 mg, 0.1 mmol) and triethylamine (TEA) (40 mg, 0.4 mmol) in DMF (1mL) was added 3-methylbutanoyl chloride (12 mg, 0.1 mmol). The mixturewas irradiated in the microwave at 135° C. for 5 minutes. The solutionwas directly purified by reverse phase HPLC (water/acetonitrilegradient) to give the title compounds (20 mg, 50% yield) as a whitesolid. MS 390 (M+H⁺).

EXAMPLE 1aN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamideDihydrochloride

A solution of tert-butyl4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate(Example 1b) (23.5 g, 58.0 mmol) in MeOH (220 mL) was treated withconcentrate HCl (110 mL) and stirred overnight at room temperature. Thesolid was collected by filtration and washed with methanol to give (18.2g, 48.1 mmol, 83% yield) of the title compound as a brown solid.

EXAMPLE 1b tert-Butyl4-(2-((6-Acelylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

A mixture of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide(Example 1c) (22 g, 73.3 mmol), tert-butyl piperazine-1-carboxylate (14g, 73.3 mmol), and K₂CO₃ (21 g, 146.6 mmol) in dry ACN was heated to 85°C. and stirred overnight under nitrogen. The reaction was diluted withEtOAc and washed successively with water and brine. The organic layerwas dried over MgSO4, filtered, and evaporated to give the titlecompound (23.6 g, 58.2 mmol, 79% yield).

EXAMPLE 1c N-(6-Acelylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide

A solution of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethanone (25 g, 139.5mmol), TEA (29.2 mL, 209.3 mmol), and DMAP (1.2 g, 9.7 mmol) in dry THF(380 mL) was cooled to 0° C. and treated dropwise with bromo acetylchloride (17.3 g, 209.3 mmol). The ice bath was then removed and thereaction was stirred overnight under nitrogen. The mixture wasconcentrated to about 150 mL of THF. The residual solution was dilutedslowly with water. After stirring for 30 min the solid product wascollected by filtration and dried to yield of title compound (41.0 g,136.5 mmol, 98% yield) as a brown solid. ¹H NMR (CDCl₃, 400 MHz): δ 2.58(s, 3H), 3.97 (s, 1H), 4.16 (s, 1H), 6.04 (s, 2H), 7.25 (d, J=14.4 Hz,1H), 8.34 (d, J=11.6 Hz, 1H), 12.68 (brs, 0.5H), 12.80 (bs, 0.5H). MS301 (M+H⁺).

EXAMPLE 2 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(5-fluoro-2-methoxybenzoyl)piperazin-1-yl)acetamide(2)

To a mixture ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochloride (Example 1a) (76 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol),EDC (38 mg, 0.2 mmol), and TEA (81 mg, 0.8 mmol) in DMF (1 mL) was added5-fluoro-2-methoxybenzoic acid (34 mg, 0.2 mmol). The mixture wasirradiated in the microwave at 150° C. for 5 minutes. The solution wasdirectly purified by reverse phase HPLC (water/acetonitrile gradient)and the clean fractions were concentrated under reduced pressure anddried under vacuum to give 40 mg (44% yield) of the title compound. MS458 (M+H+).

EXAMPLE 3 Synthesis of Propyl4-(2-4-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate(3)

Prepared in a similar manner as in Example 1 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetami dedihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol),and propyl carbonochloridate (25 mg, 0.2 mmol) to give 16 mg (25% yield)of the title compound. MS 392 (M+H⁺).

EXAMPLE 4 Synthesis of4-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-N-isopropylpiperazine-1-carboxamide(4)

Prepared in a similar manner as in Example 1 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol),and 2-isocyanatopropane (17 mg, 0.2 mmol) to give 23 mg (30% yield) ofthe title compound. MS 391 (M+H⁺).

EXAMPLE 5 Synthesis ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-(isopropylsulfonyl)piperazin-1-yl)acetamide(5)

Prepared in a similar manner as in Example 1 from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamide dihydrochloride (76 mg,0.2 mmol), TEA (40 mg, 0.4 mmol), and propane-2-sulfonyl chloride (28mg, 0.2 mmol) to give 42 mg (10% yield) of the title compound. MS 412(M+H⁺).

EXAMPLE 6 Synthesis ofN-(6-Methoxybenzo[d][1,3]dioxol-5-yl)-2-(4-(3-methylbutanoyl)piperazin-1-yl)acetamide(6)

N-(6-Methoxybenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochloride (Example 6a) (73 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol),EDC (38 mg, 0.2 mmol), and TEA (81 mg, 0.8 mmol) were suspended in DMF(1 mL) followed by addition of 3-methylbutanoic acid (20 mg, 0.2 mmol).The mixture was irradiated in the microwave at 150° C. for 5 minutes.The solution was directly purified by reverse phase HPLC(water/acetonitrile gradient) to give 29 mg (38% yield) of the titlecompound. MS 378 (M+H⁺).

EXAMPLE 6aN-(6-Methoxybenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochlorides

Prepared in a similar manner as in Example 1a from tert-butyl4-(2-((6-methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate(Example 6b) (1.29 g, 3.28 mmol) to afford the title compound as ayellow solid (1.20 g, quantitative yield).

EXAMPLE 6b tert-Butyl4-(24(6-methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

Prepared in a similar manner as in Example 1b from2-bromo-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide (Example 6c)(1.58 g, 5.5 mmol) and tert-butyl piperazine-1-carboxylate to afford thetitle compound as a yellowish solid (1.30 g, 3.30 mmol, 60% yield).

EXAMPLE 6c 2-Bromo-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide

Prepared in a similar manner as in Example 1c from6-methoxybenzo[d][1,3]-dioxol-5-amine (0.92 g, 5.5 mmol) and bromoacetylchloride to yield the desired product (1.60 g, quantitative yield) as agreyish solid. MS 289 (M+H⁺).

Compounds in Table 2 were prepared in a similar manner as in Example 1,Example 2, and/or Example 6 from the corresponding amine hydrochloridesdescribed herein and commercially available electrophiles (e.g.carboxylic acids, acyl chlorides, chloroformates, isocyanates, andsulfonylchlorides).

TABLE 2 Obs. Mol hT2R54 Ion; MS IC50 SID Structure (M + H⁺) (uM) ¹H NMR(400 MHz) 1

390 0.016 (DMSO-d₆) δ 1.40 (d, J = 6.6 Hz, 6H), 2.52-2.61 (m, 1H), 2.69(d, J = 6.8 Hz, 2H), 2.96-3.02 (m, 2H), 3.03-3.09 (m, 5H), 3.60 (s, 2H),4.08-4.30 (m, 4H), 6.57 (s, 2H), 7.97 (s, 1H), 8.93 (s, 1H), 13.27 (s,1H). 2

458 0.027 (DMSO-d₆) δ 2.42-2.50 (m, 2H), 2.53-2.60 (m, 5H), 3.18 (s,2H), 3.23-3.32 (m, 2H), 3.70- 3.85 (m, 5H), 6.14 (s, 2H), 7.05- 7.18 (m,2H), 7.23 (ddd, J = 9.1, 8.4, 3.2 Hz, 1H), 7.62 (s, 1H), 8.32 (s, 1H),12.68 (s, 1H). 3

392 0.015 (DMSO-d₆) δ 0.89 (t, J = 7.4 Hz, 3H), 1.58 (m, 2H), 2.48 (m,4H), 2.57 (s, 3H), 3.16 (s, 2H), 3.52 (s, 4H), 3.96 (t, J = 6.6 Hz, 2H),6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.66 (s, 1H). 4

392 0.034 (DMSO-d₆) δ 1.05 (d, J = 6.6 Hz, 6H), 2.45 (t, J = 4.9 Hz,4H), 2.57 (s, 3H), 3.14 (s, 2H), 3.42 (t, J = 4.9 Hz, 4H), 3.69-3.82 (m,1H), 6.14 (s, 1H), 6.19 (d, J = 7.5 Hz, 1H), 7.61 (s, 1H), 8.34 (s, 1H),12.64 (s, 1H). 5

412 0.130 (DMSO-d₆) δ 1.26 (d, J = 6.8 Hz, 6H), 2.53-2.61 (m, 7H), 3.19(s, 2H), 3.36-3.44 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H),12.67 (s, 1H). 6

378 0.49 (DMSO-d₆) δ 0.90 (d, J = 6.6 Hz, 6H), 1.98 (m, 1H), 2.20 (d, J= 7.0 Hz, 2H), 2.43-2.58 (m, 2H), 3.13 (s, 2H), 3.48-3.54 (m, 4H), 3.82(s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77 (s, 1H), 9.52 (s, 1H). 7

348 0.09 (DMSO-d₆) δ 2.01 (s, 3H), 2.40- 2.48 (m, 2H), 2.50-2.55 (m,2H), 2.58 (s, 3H), 3.16 (s, 2H), 3.53-3.63 (m, 4H), 6.14 (s, 2H), 7.62(s, 1H), 8.34 (s, 1H), 12.68 (s, 1H). 8

362 0.05 (DMSO-d₆) δ 0.99 (t, J = 7.4 Hz, 3H), 2.34 (q, J = 7.3 Hz, 2H),2.46 (br. s, 4H), 2.57 (s, 3H), 3.17 (br. s, 2H), 3.58 (br. s, 4H), 6.15(s, 2H), 7.61 (s, 1H), 8.32 (br. s, 1H), 12.66 (br. s, 1H). 9

376 0.029 (DMSO-d₆) δ 0.89 (t, J = 7.4 Hz, 3H), 1.51 (h, J = 7.4 Hz,2H), 2.30 (t, J = 7.4 Hz, 2H), 2.39- 2.48 (m, 2H), 2.52-2.54 (m, 2H),2.57 (s, 3H), 3.16 (s, 2H), 3.59 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H),8.34 (s, 1H), 12.67 (s, 1H). 10

390 0.009 (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.25-1.34 (m, 2H), 1.44-1.51 (m, 2H), 2.31 (t, J = 7.2 Hz, 2H), 2.45 (t, J = 4.3 Hz, 2H), 2.53(m, 2H), 2.57 (s, 3H), 3.16 (s, 2H), 3.59 (m, 4H), 6.14 (s, 2H), 7.62(s, 1H), 8.33 (s, 1H), 12.67 (s, 1H). 11

376 0.04 (DMSO-d₆) δ 1.00 (d, J = 6.7 Hz, 6H), 2.45-2.47 (m, 2H),2.53-2.54 (m, 2H), 2.58 (s, 3H), 2.88 (hept, J = 6.7 Hz, 1H), 3.17 (s,2H), 3.61-3.65 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68(s, 1H). 12

374 0.04 (DMSO-d₆) δ 0.68-0.76 (m, 4H), 1.99 (tt, J = 7.7, 4.8 Hz, 1H),2.47 (br. s, 2H), 2.56 (br. s, 2H), 2.58 (s, 3H), 3.18 (s, 2H), 3.61(br. s, 2H), 3.83 (br. s, 2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H),12.69 (s, 1H). 13

390 0.023 (DMSO-d₆) δ 1.20 (s, 9H), 2.48 (br., s, 4H), 2.58 (s, 3H),3.16 (s, 2H), 3.69 (br. s, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s,1H), 12.69 (s, 1H). 14

404 0.08 (DMSO-d₆) δ 0.99 (s, 9H), 2.24 (s, 2H), 2.44-2.47 (m, 2H), 2.52(m, 2H), 2.57 (s, 3H), 3.16 (s, 2H), 3.64 (m, 4H), 6.14 (s, 2H), 7.61(s, 1H), 8.33 (s, 1H), 12.66 (s, 1H). 15

388 0.024 (DMSO-d₆) δ 0.97-0.13 (m, 2H), 0.43-0.47 (m, 2H), 0.90- 1.00(m, 1H), 2.27 (d, J = 6.8 Hz, 2H), 2.45-2.47 (m, 2H), 2.52 (m, 2H), 2.57(s, 3H), 3.16 (s, 2H), 3.57-3.62 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H),8.34 (s, 1H), 12.67 (s, 1H). 16

402 0.029 (DMSO-d₆) δ 1.47-1.82 (m, 8H), 2.42-2.48 (m, 2H), 2.49- 2.55(m, 2H), 2.58 (s, 3H), 2.90- 3.05 (m, 1H), 3.16 (s, 2H), 3.55- 3.70 (m,4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H), 12.68 (s, 1H). 17

416 0.15 (DMSO-d₆) δ 1.10-1.16 (m, 1H), 1.24-1.38 (m, 4H), 1.62-1.70 (m,5H), 2.45 (m, 2H), 2.52 (m, 2H), 2.57 (s, 3H), 2.61 (m, 1H), 3.16 (s,2H), 3.60-3.63 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.67(s, 1H). 18

364 0.216 (DMSO-d₆) δ 2.45-2.52 (m, 4H), 2.58 (s, 3H), 3.17 (s, 2H),3.48- 3.50 (m, 2H), 3.61-3.64 (m, 2H), 4.10 (d, J = 5.3 Hz, 2H), 4.58(t, J = 5.5 Hz, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s,1H). 19

378 0.06 (DMSO-d₆) δ 2.47-2.48 (m, 2H), 2.52 (m, 2H), 2.58 (s, 3H), 3.16(s, 2H), 3.29 (s, 3H), 3.53 (m, 2H), 3.60 (m, 2H), 4.10 (s, 2H), 6.14(s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H). 20

406 0.17 (DMSO-d₆) δ 1.10 (d, J = 6.1 Hz, 6H), 2.47 (m, 2H), 2.54 (m,2H), 2.58 (s, 3H), 3.17 (2H), 3.56-3.63 (m, 5H), 4.10 (s, 2H), 6.14 (s,2H), 7.62 (s, 1H), 8.34 (s, 1H), 12.68 (s, 1H). 21

422 0.179 (DMSO-d₆) δ 2.48 (m, 2H), 2.52 (m, 2H), 2.58 (s, 3H), 3.16 (s,2H), 3.25 (s, 2H), 3.46 (dd, J = 6.2, 3.3 Hz, 2H), 3.55-3.59 (m, 6H),4.16 (s, 2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H).22

404 0.021 (DMSO-d₆)) δ 1.74-1.89 (m, 2H), 1.92-2.10 (m, 2H), 2.43- 2.56(m, 4H), 2.58 (s, 3H), 3.16 (s, 2H), 3.56-3.81 (m, 6H), 4.67 (dd, J =7.7, 5.6 Hz, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s,1H). 23

418 0.018 (DMSO-d₆) δ 1.48-1.83 (m, 6H), 2.46-2.54 (m, 4H), 2.58 (s,3H), 3.16 (s, 2H), 3.43-3.49 (m, 1H), 3.60-3.65 (m, 4H), 3.84- 3.87 (m,1H), 4.14 (dd, J = 9.3, 3.3 Hz, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34(s, 1H), 12.68 (s, 1H). 24

418 0.336 (DMSO-d₆) δ 1.44-1.66 (m, 4H), 2.44 (m, 2H), 2.51 (m, 2H),2.56 (s, 3H), 2.80-2.93 (m, 1H), 3.15 (s, 2H), 3.36 (td, J = 11.5, 2.6Hz, 2H), 3.55-3.62 (m, 2H), 3.62-3.70 (m, 2H), 3.82 (ddd, J = 11.1, 3.8,1.8 Hz, 2H), 6.12 (s, 2H), 7.60 (s, 1H), 8.31 (s, 1H), 12.65 (s, 1H). 25

431 4.36 26

491 2.06 27

418 0.176 (DMSO-d₆) δ 1.66-1.77 (m, 4H), 2.43-2.49 (m, 2H), 2.53 (m,2H), 2.58 (s, 3H), 2.61 (m, 4H), 3.16 (s, 2H), 3.44 (s, 2H), 3.56-3.62(m, 2H), 3.62-3.68 (m, 2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H),12.67 (s, 1H). 28

433 0.107 (DMSO-d₆) δ 2.40 (br t, J = 4.9 Hz, 4H), 2.46 (br t, J = 4.9Hz, 2H), 2.54 (br t, J = 5.2 Hz, 2H), 2.58 (s, 3H), 3.16 (s, 4H), 3.50-3.63 (m, 6H), 3.70 (t, J = 4.9 Hz, 2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33(s, 1H), 12.67 (s, 1H). 29

378 0.311 (DMSO-d₆) δ 1.02-1.22 (m, 5H), 1.66 (d, J = 13.1 Hz, 2H),1.87-2.02 (m, 1H), 2.31 (d, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.66- 2.89(m, 2H), 3.90-4.06 (m, 4H), 6.14 (s, 2H), 7.56 (s, 1H), 8.11 (s, 1H),11.81 (s, 1H). 30

392 0.04 (DMSO-d₆) δ 1.19 (d, J = 6.2 Hz, 6H), 2.47-2.48 (m, 4H), 2.57(s, 3H), 3.16 (s, 2H), 3.50 (t, J = 4.8 Hz, 4H), 4.78 (m, 1H), 6.14 (s,2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.65 (s, 1H). 31

426 0.262 (DMSO-d₆) δ 2.60 (m, 7H), 3.22 (s, 2H), 3.60 (br. s, 2H), 3.75(br. s, 2H), 6.14 (s, 2H), 7.07-7.19 (m, 2H), 7.22 (tt, J = 7.0, 1.1 Hz,1H), 7.35-7.44 (m, 2H), 7.63 (s, 1H), 8.35 (s, 1H), 12.70 (s, 1H). 32

440 0.021 (DMSO-d₆) δ 2.47-2.48 (m, 4H), 2.57 (s, 3H), 3.15 (s, 2H),3.47-3.50 (m, 4H), 4.25 (d, J = 5.8 Hz, 2H), 6.14 (s, 2H), 7.12 (t, J =5.8 Hz, 1H), 7.16-7.33 (m, 5H), 7.61 (s, 1H), 8.34 (s, 1H), 12.65 (s,1H). 33

425 0.05 (DMSO-d₆) δ 2.54 (t, J = 4.7 Hz, 4H), 2.59 (s, 3H), 3.19 (s,2H), 3.60 (t, J = 4.7 Hz, 4H), 6.14 (s, 2H), 6.93 (tt, J = 7.4, 1.2 Hz,1H), 7.18-7.28 (m, 2H), 7.41-7.49 (m, 2H), 7.63 (s, 1H), 8.35 (s, 1H),8.55 (s, 1H), 12.68 (s, 1H). 34

410 0.02 (DMSO-d₆) δ 2.52-2.55 (m, 4H), 2.58 (s, 3H), 3.18 (s, 2H), 3.49(br. s, 2H), 3.78 (br. s, 2H), 6.14 (s, 2H), 7.40-7.46 (m, 5H), 7.62 (s,1H), 8.33 (s, 1H), 12.68 (s, 1H). 35

416 0.04 (DMSO-d₆) δ 2.53-2.64 (m, 7H), 3.20 (s, 0H), 3.74-3.86 (m, 4H),6.14 (s, 1H), 7.13 (dd, J = 5.0, 3.7 Hz, 1H), 7.44 (dd, J = 3.7, 1.1 Hz,1H), 7.63 (s, 1H), 7.76 (dd, J = 5.0, 1.1 Hz, 1H), 8.34 (s, 1H), 12.71(s, 1H). 36

400 0.004 (DMSO-d₆) δ 2.53-2.62 (m, 7H), 3.19 (s, 2H), 3.66-3.91 (m,4H), 6.14 (s, 2H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H), 7.01 (dd, J = 3.5,0.8 Hz, 1H), 7.63 (s, 1H), 7.84 (dd, J = 1.8, 0.8 Hz, 1H), 8.34 (s, 1H),12.71 (s, 1H). 37

416 0.023 (DMSO-d₆) δ 2.50-2.65 (m, 7H), 3.18 (s, 3H), 3.47-3.92 (m,4H), 6.14 (s, 3H), 7.19-7.26 (m, 1H), 7.58-7.67 (m, 3H), 7.81 (dd, J =2.9, 1.3 Hz, 1H), 8.33 (s, 1H), 12.70 (s, 1H). 38

426 0.05 (DMSO-d₆) δ 2.58 (m, 7H), 3.18 (s, 2H), 3.48 (br. s, 2H), 3.74(br. s, 2H), 6.14 (s, 2H), 6.75 (dd, J = 2.5, 1.5 Hz, 1H), 6.81 (ddt, J= 13.2, 7.5, 1.3 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.62 (s, 1H), 8.33(s, 1H), 9.70 (s, 1H), 12.68 (s, 1H). 39

411 0.07 (DMSO-d₆) δ 2.50-2.55 (m, 2H), 2.57-2.64 (m, 5H), 3.19 (s, 2H),3.38-3.48 (m, 2H), 3.75- 3.86 (m, 2H), 6.14 (s, 2H), 7.38- 7.46 (m, 2H),7.62 (s, 1H), 8.32 (s, 1H), 8.64-8.70 (m, 2H), 12.68 (s, 1H). 40

426 0.08 (DMSO-d₆) δ 2.53 (m, 4H), 2.58 (s, 3H), 3.18 (s, 2H), 3.77 (br.s, 4H), 6.13 (s, 2H), 6.82-6.88 (m, 2H), 7.13 (dd, J = 7.5, 1.8 Hz, 1H),7.22 (ddd, J = 8.2, 7.3, 1.8 Hz, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 9.80(s, 1H), 12.68 (s, 1H). 41

440 0.04 (DMSO-d₆) δ 2.42-2.50 (m, 2H), 2.55-2.58 (m, 5H), 3.17 (s, 2H),3.25-3.30 (m, 2H), 3.76-3.81 (m, 5H), 6.13 (s, 2H), 7.00 (td, J = 7.4,0.9 Hz, 1H), 7.08 (dd, J = 8.5, 0.9 Hz, 1H), 7.19 (dd, J = 7.4, 1.7 Hz,1H), 7.39 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.61 (s, 1H), 8.32 (s, 1H),12.67 (s, 1H). 42

411 0.06 (DMSO-d₆) δ 2.54 (br. s, 2H), 2.58-2.61 (m, 5H), 3.19 (s, 2H),3.49 (br. s, 2H), 3.80 (br. s, 2H), 6.14 (s, 2H), 7.48 (ddd, J = 7.8,4.9, 0.9 Hz, 1H), 7.62 (s, 1H), 7.86 (ddd, J = 7.8, 2.2, 1.7 Hz, 1H),8.33 (s, 1H), 8.63 (dd, J = 2.2, 0.9 Hz, 1H), 8.65 (dd, J = 4.9, 1.7 Hz,1H), 12.68 (s, 1H). 43

426 0.08 (DMSO-d₆) δ 2.53 (m, 4H), 2.58 (s, 3H), 3.17 (s, 2H), 3.64 (br.s, 4H), 6.14 (s, 2H), 6.79 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz,2H), 7.62 (s, 1H), 8.33 (s, 1H), 9.87 (br. s, 1H), 12.68 (s, 1H). 44

428 0.05 (DMSO-d₆) δ 2.48-2.50 (m, 2H), 2.58-2.61 (m, 5H), 3.19 (s, 2H),3.35-3.43 (m, 2H), 3.74-3.86 (m, 2H), 6.14 (s, 2H), 7.26-7.35 (m, 2H),7.39-7.46 (m, 1H), 7.51 (m, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s,1H). 45

428 0.028 (DMSO-d₆) δ 2.54-2.58 (m, 7H), 3.18 (s, 2H), 3.50 (br. s, 2H),3.76 (br. s, 2H), 6.14 (s, 2H), 7.28 (t, J = 8.9 Hz, 2H), 7.49 (dd, J =8.8, 5.5 Hz, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H). 46

428 0.026 (DMSO-d₆) δ 2.58 (m, 7H), 3.18 (s, 2H), 3.46 (br. s, 2H), 3.78(br. s, 2H), 6.14 (s, 2H), 7.17-7.37 (m, 3H), 7.42-7.55 (m, 1H), 7.62(s, 1H), 8.32 (s, 1H), 12.68 (s, 1H). 47

440 0.021 (DMSO-d₆) δ 2.51-2.57 (m, 4H), 2.58 (s, 3H), 3.18 (s, 2H),3.45-3.74 (m, 4H), 3.79 (s, 3H), 6.14 (s, 2H), 6.94-7.03 (m, 2H),7.34-7.43 (m, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.69 (s, 1H). 48

440 0.013 (DMSO-d₆) δ 2.58 (m, 7H), 3.18 (s, 2H), 3.48 (br. s, 2H), 3.78(m, 5H), 6.14 (s, 2H), 6.92-6.97 (m, 2H), 6.98- 7.05 (m, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.62 (s, 1H), 8.32 (s, 1H), 12.68 (s, 1H). 49

411 0.1 (DMSO-d₆) δ 2.50-2.53 (m, 2H), 2.57 (s, 3H), 2.60 (t, J = 4.8Hz, 2H), 3.17 (s, 2H), 3.53 (t, J = 5.0 Hz, 2H), 3.80 (t, J = 4.9 Hz,2H), 6.12 (s, 2H), 7.46 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.57 (dt, J =7.8, 1.1 Hz, 1H), 7.60 (s, 1H), 7.91 (td, J = 7.7, 1.8 Hz, 1H), 8.31 (s,1H), 8.57 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 12.69 (s, 1H). 50

440 0.402 (DMSO-d₆) δ 2.49-2.64 (m, 5H), 3.14-3.21 (m, 3H), 3.28- 3.34(m, 1H), 3.49 (br s, 2H), 3.78 (br s, 2H), 4.53 (d, J = 5.2 Hz, 2H),5.23-5.31 (m, 1H), 6.14 (s, 2H), 7.23-7.30 (m, 1H), 7.33-7.45 (m, 3H),7.62 (s, 1H), 8.33 (s, 1H), 12.69 (s, 1H). 51

454 0.234 (DMSO-d₆) δ 2.39-2.63 (m, 8H), 3.18 (s, 2H), 3.30 (s, 3H),3.48 (br s, 1.5H), 3.78 (br s, 1.5H), 4.45 (s, 2H), 6.14 (s, 2H),7.30-7.37 (m, 2H), 7.37-7.48 (m, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.68(s, 1H). 52

424 0.051 (DMSO-d₆) δ 2.39-2.48 (m, 4H), 2.56 (s, 3H), 3.13 (s, 2H),3.7-3.68 (m, 4H), 3.74 (s, 2H), 6.14 (s, 2H), 7.18-7.36 (m, 5H), 7.61(s, 1H), 8.33 (s, 1H), 12.66 (s, 1H). 53

440 0.018 (DMSO-d₆) δ 2.45-2.46 (m, 4H), 2.57 (s, 3H), 3.14 (s, 2H),3.60 (s, 2H), 3.64 (m, 4H), 6.14 (s, 2H), 6.74 (td, J = 7.4, 1.2 Hz,1H), 6.80 (dd, J = 8.5, 1.2 Hz, 1H), 6.97-7.13 (m, 2H), 7.61 (s, 1H),8.33 (s, 1H), 9.53 (br. s, 1H), 12.66 (s, 1H). 54

454 0.024 (DMSO-d₆) δ 2.46-2.47 (m, 4H), 2.58 (s, 3H), 3.15 (s, 2H),3.62 (m, 6H), 3.77 (s, 3H), 6.14 (s, 2H), 6.89 (td, J = 7.4, 1.1 Hz,1H), 6.97 (dd, J = 8.3, 1.1 Hz, 1H), 7.11 (dd, J = 7.5, 1.7 Hz, 1H),7.23 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 12.67(s, 1H). 55

442 0.07 (DMSO-d₆) δ 2.48 (m, 2H), 2.52- 2.57 (m, 2H), 2.58 (s, 3H),3.18 (s, 2H), 3.59-3.66 (m, 2H), 3.66- 3.73 (m, 2H), 3.76 (s, 2H), 6.14(s, 2H), 7.09-7.20 (m, 2H), 7.22- 7.34 (m, 2H), 7.62 (s, 1H), 8.34 (s,1H), 12.68 (s, 1H). 56

425 0.08 (DMSO-d₆) δ 2.48 (m, 2H), 2.51- 2.54 (m, 2H), 2.57 (s, 3H),3.17 (s, 2H), 3.63 (m, 2H), 3.70 (m, 2H), 3.79 (s, 2H), 6.14 (s, 2H),7.33 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.59-7.67 (m, 2H), 8.33 (s, 1H),8.43-8.44 (m, 2H), 12.67 (s, 1H). 57

440 0.1 (DMSO-d₆) δ 2.38-2.48 (m, 4H), 2.56 (s, 3H), 3.13 (s, 2H),3.61-3.64 (s, 6H), 6.13 (s, 2H), 6.56-6.72 (m, 4H), 7.09 (t, J = 8.0 Hz,1H), 7.61 (s, 1H), 8.32 (s, 1H), 9.33 (s, 1H), 12.65 (s, 1H). 58

454 0.06 (DMSO-d₆) δ 2.44 (m, 4H), 2.56 (s, 3H), 3.14 (s, 2H), 3.63 (q,J = 4.1 Hz, 4H), 3.71 (s, 2H), 3.73 (s, 3H), 6.13 (s, 2H), 6.80-6.82 (m,3H), 7.16-7.28 (m, 1H), 7.61 (s, 1H), 8.32 (s, 1H), 12.65 (s, 1H). 59

442 0.2 (DMSO-d₆) δ 2.43-2.49 (m, 4H), 2.57 (s, 3H), 3.15 (s, 2H), 3.64(dt, J = 13.8, 5.0 Hz, 4H), 3.77 (s, 2H), 6.14 (s, 2H), 7.01- 7.11 (m,3H), 7.30-7.40 (m, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 12.67 (s, 1H). 60

425 0.08 (DMSO-d₆) δ 2.47-2.48 (m, 4H), 2.57 (s, 3H), 3.16 (s, 3H), 3.65(m, 4H), 3.80 (s, 2H), 6.14 (s, 2H), 7.22-7.29 (m, 2H), 7.61 (s, 1H),8.33 (s, 1H), 8.44-8.54 (m, 2H), 12.66 (s, 1H). 61

440 0.05 (DMSO-d₆) δ 2.42 (dt, J = 14.5, 4.8 Hz, 4H), 2.56 (s, 3H), 3.13(s, 2H), 3.56-3.65 (m, 4H), 6.14 (s, 2H), 6.65-6.73 (m, 2H), 6.98- 7.06(m, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 9.26 (s, 1H), 12.65 (s, 1H). 62

454 0.2 (DMSO-d₆) δ 2.41-2.46 (m, 4H), 2.46 (s, 3H), 3.13 (s, 2H),3.60-3.65 (m, 6H), 3.73 (s, 3H), 6.13 (s, 2H), 6.87 (d, J = 8.7 Hz, 2H),7.15 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 8.32 (s, 1H), 12.65 (s, 1H). 63

442 0.4 (DMSO-d₆) δ 2.42-2.48 (m, 4H), 2.57 (s, 3H), 3.15 (s, 2H), 3.64(dt, J = 13.5, 4.7 Hz, 4H), 3.73 (s, 2H), 6.14 (s, 2H), 7.13 (t, J = 8.9Hz, 2H), 7.26 (dd, J = 8.9, 5.6 Hz, 2H), 7.61 (s, 1H), 8.33 (s, 1H),12.66 (s, 1H). 64

414 0.1 (DMSO-d₆) δ 2.46-2.49 (m, 4H), 2.57 (s, 3H), 3.16 (s, 2H), 3.61(t, J = 4.9 Hz, 2H), 3.66 (t, J = 5.0 Hz, 2H), 3.80 (s, 2H), 6.14 (s,2H), 6.21 (dd, J = 3.2, 0.8 Hz, 1H), 6.39 (dd, J = 3.1, 1.9 Hz, 1H),7.56 (dd, J = 1.9, 0.9 Hz, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 12.67 (s,1H). 65

430 0.03 (DMSO-d₆) δ 2.43-2.49 (m, 4H), 2.57 (s, 3H), 3.15 (s, 2H), 3.62(t, J = 4.7 Hz, 2H), 3.68 (t, J = 4.9 Hz, 2H), 3.97 (s, 2H), 6.14 (s,2H), 6.93 (m, 1H), 6.96 (dd, J = 5.1, 3.4 Hz, 1H), 7.38 (dd, J = 5.1,1.3 Hz, 1H), 7.61 (s, 1H), 8.33 (s, 1H), 12.67 (s, 1H). 66

414 0.017 (DMSO-d₆) δ 2.54 (t, J = 4.9 Hz, 4H), 2.59 (s, 3H), 3.18 (s,2H), 3.76 (m, 4H), 3.85 (s, 3H), 6.14 (s, 2H), 7.62 (s, 1H), 7.67 (d, J= 0.7 Hz, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 12.71 (s, 1H). 67

430 0.015 (DMSO-d₆) δ 2.46 (s, 3H), 2.53- 2.58 (m, 4H), 2.59 (s, 3H),3.19 (s, 2H), 3.79 (s, 4H), 6.14 (s, 2H), 6.82 (dd, J = 3.6, 1.1 Hz,1H), 7.24 (d, J = 3.5 Hz, 1H), 7.62 (s, 1H), 8.34 (s, 1H), 12.70 (s,1H). 68

430 0.03 (DMSO-d₆) δ 2.21 (s, 3H), 2.52- 2.57 (m, 4H), 2.58 (s, 3H),3.19 (s, 3H), 3.64 (br s, 4H), 6.14 (s, 2H), 6.94 (d, J = 4.9 Hz, 1H),7.58 (d, J = 5.0 Hz, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H). 69

429 0.04 (DMSO-d₆) δ 2.20 (s, 3H), 2.39 (s, 3H), 2.55 (br s, 4H), 2.58(s, 3H), 3.19 (s, 2H), 3.62 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.32(s, 1H), 12.66 (s, 1H). 70

401 0.02 (DMSO-d₆) δ 2.55-2.58 (m, 5H), 2.60-2.63 (m, 2H), 3.20 (s, 2H),3.68-3.70 (m, 2H), 3.81- 3.83 (m, 2H), 6.14 (s, 2H), 6.85 (d, J = 1.7Hz, 1H), 7.62 (s, 1H), 8.33 (s, 1H), 9.09 (d, J = 1.7 Hz, 1H), 12.70 (s,1H). 71

414 0.05 (DMSO-d₆) δ 2.55 (br s, 4H), 2.59 (s, 3H), 3.18 (s, 2H), 3.77(br. s, 2H), 3.88 (s, 3H), 4.07 (br s, 2H), 6.14 (s, 2H), 6.55 (d, J =2.2 Hz, 1H), 7.62 (s, 1H), 7.76 (d, J = 2.2 Hz, 1H), 8.34 (s, 1H), 12.71(s, 1H). 72

401 0.06 (DMSO-d₆) δ 2.56-2.62 (m, 7H), 3.20 (s, 2H), 3.81 (br s, 4H),6.14 (s, 2H), 7.63 (s, 1H), 7.74 (s, 1H), 8.34 (s, 1H), 8.56 (s, 1H),12.71 (s, 1H). 73

430 0.08 (DMSO-d₆) δ 2.22 (d, J = 1.0 Hz, 3H), 2.58 (m, 7H), 3.19 (s,2H), 3.71-3.86 (m, 4H), 6.14 (s, 2H), 7.26 (d, J = 1.4 Hz, 1H), 7.31-7.38 (m, 1H), 7.62 (s, 1H), 8.34 (s, 1H), 12.71 (s, 1H). 74

428 0.2 (DMSO-d₆) δ 2.18 (s, 3H), 2.52- 2.54 (m, 4H), 2.58 (s, 3H), 3.18(s, 2H), 3.62-3.72 (m, 4H), 3.75 (s, 3H), 6.14 (s, 2H), 7.62 (s, 1H),7.86 (s, 1H), 8.34 (s, 1H), 12.69 (s, 1H). 75

402 0.1 (DMSO-d₆) δ 2.54-2.61 (m, 7H), 3.19 (s, 2H), 3.70-3.73 (m, 4H),6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.69 (s, 1H). 76

429 0.07 (DMSO-d₆) δ 2.38 (s, 3H), 2.41 (s, 3H), 2.52-2.57 (m, 4H), 2.58(s, 3H), 3.18 (s, 2H), 3.72 (br s, 2H), 3.97 (br s, 2H), 6.14 (s, 2H),7.62 (s, 1H), 8.34 (s, 1H), 12.69 (s, 1H). 77

413 0.03 (DMSO-d₆) δ 2.51-2.53 (m, 4H), 2.58 (s, 3H), 3.17 (s, 2H), 3.62(s, 3H), 3.76 (m, 4H), 6.14 (s, 2H), 6.21 (dd, J = 2.8, 1.7 Hz, 1H),6.72 (t, J = 2.4 Hz, 1H), 7.11 (t, J = 1.9 Hz, 1H), 7.62 (s, 1H), 8.34(s, 1H), 12.70 (s, 1H). 78

415 0.03 (DMSO-d₆) δ 2.58-2.60 (m, 7H), 3.19 (s, 2H), 3.79 (br s, 2H),4.08 (s, 3H), 4.16 (br s, 2H), 6.14 (s, 2H), 7.63 (s, 1H), 8.34 (s, 1H),8.49 (s, 1H), 12.72 (s, 1H). 79

400 0.03 (DMSO-d₆) δ 2.54 (t, J = 5.0 Hz, 4H), 2.58 (s, 3H), 3.18 (s,2H), 3.63-3.79 (m, 4H), 6.14 (s, 2H), 6.68 (dd, J = 1.9, 0.8 Hz, 1H),7.62 (s, 1H), 7.74 (t, J = 1.7 Hz, 1H), 8.06 (dd, J = 1.6, 0.9 Hz, 1H),8.34 (s, 1H), 12.70 (s, 1H). 80

450 0.5 (DMSO-d₆) δ 2.60 (s, 3H), 2.62 (t, J = 4.9 Hz, 4H), 3.22 (s,2H), 3.88 (br. s, 4H), 6.14 (s, 2H), 7.33 (ddd, J = 8.0, 7.2, 1.0 Hz,1H), 7.41-7.48 (m, 2H), 7.63 (s, 1H), 7.67 (dq, J = 8.4, 0.9 Hz, 1H),7.75 (ddd, J = 7.8, 1.4, 0.7 Hz, 1H), 8.34 (s, 1H), 12.73 (s, 1H). 81

414 0.004 (DMSO-d₆) δ 2.32 (s, 3H), 2.55- 2.59 (m, 7H), 3.19 (s, 2H),3.81 (br s, 4H), 6.14 (s, 2H), 6.24- 6.25 (m, 1H), 6.90 (d, J = 3.3 Hz,1H), 7.63 (s, 1H), 8.34 (s, 1H), 12.71 (s, 1H). 82

378 0.54 (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.40-1.53 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.46 (t, J = 5.2 Hz, 2H), 2.53(m, 2H), 3.13 (s, 2H), 3.45-3.55 (m, 4H), 3.82 (s, 3H), 5.95 (s, 2H),6.91 (s, 1H), 7.78 (s, 1H), 9.53 (s, 1H). 83

366 0.52 (DMSO-d₆) δ 1.19 (t, J = 7.1 Hz, 3H), 2.49-2.51 (m, 4H), 3.13(s, 2H), 3.42-3.45 (m, 4H), 3.82 (s, 3H), 4.05 (q, J = 7.1 Hz, 2H), 5.95(s, 2H), 6.91 (s, 1H), 7.79 (s, 1H), 9.51 (s, 1H). 84

380 0.24 (DMSO-d₆) δ 0.89 (t, J = 7.4 Hz, 3H), 1.58 (h, J = 7.4 Hz, 2H),3.13 (s, 2H), 3.43 (m, 4H), 3.82 (s, 3H), 3.96 (t, J = 6.6 Hz, 2H), 5.95(s, 2H), 6.91 (s, 1H), 7.78 (s, 1H), 9.51 (s, 1H). 85

392 1.16 (DMSO-d₆) δ 1.77-1.89 (m, 2H), 1.94-2.08 (m, 2H), 2.52- 2.55(m, 4H), 3.13 (s, 2H), 3.51- 3.64 (m, 4H), 3.70-3.78 (m, 2H), 3.82 (s,3H), 4.66 (dd, J = 7.6, 5.7 Hz, 1H), 5.95 (s, 2H), 6.91 (s, 1H), 7.78(s, 1H), 9.53 (s, 1H). 86

406 1.14 (DMSO-d₆) δ 1.46-1.57 (m, 6H), 2.51 (m, 4H), 3.11 (s, 2H),3.44-3.53 (m, 6H), 3.80 (s, 3H), 4.11 (dd, J = 9.1, 3.5 Hz, 1H), 5.93(s, 2H), 6.89 (s, 1H), 7.76 (s, 1H), 9.51 (s, 1H). 87

420 1.04 (DMSO-d₆) δ 1.19 (qd, J = 12.0, 4.3 Hz, 2H), 1.52-1.64 (m, 2H),1.91 (m, 1H), 2.26 (d, J = 6.9 Hz, 2H), 2.42-2.53 (m, 4H), 3.13 (s, 2H),3.25-3.30 (m, 2H), 3.51- 3.53 (m, 4H), 3.79 (m, 2H), 3.82 (s, 3H), 5.95(s, 2H), 6.91 (s, 1H), 7.77 (s, 1H), 9.52 (s, 1H). 88

388 0.13 (DMSO-d₆) δ 2.58-2.60 (m, 4H), 3.16 (s, 2H), 3.73 (br s, 4H),3.83 (s, 3H), 5.95 (s, 2H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H), 6.92 (s,1H), 7.01 (dd, J = 3.5, 0.8 Hz, 1H), 7.78 (s, 1H), 7.85 (dd, J = 1.8,0.8 Hz, 1H), 9.54 (s, 1H). 89

402 0.08 (DMSO-d₆) δ 2.32 (s, 3H), 2.56- 2.59 (m, 4H), 3.16 (s, 2H),3.73 (br s, 4H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (dd, J = 3.3, 1.0 Hz,1H), 6.90 (d, J = 3.3 Hz, 1H), 6.91 (s, 1H), 7.78 (s, 1H), 9.54 (s, 1H).90

416 0.20 (DMSO-d₆) δ 2.58 (m, 2H), 2.60- 2.62 (m, 2H), 3.16 (s, 2H),3.28- 3.30 (m, 2H), 3.71-3.73 (m, 2H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91(s, 1H), 7.28-7.33 (m, 2H), 7.42 (td, J = 7.2, 1.8 Hz, 1H), 7.48-7.54(m, 1H), 7.76 (s, 1H), 9.51 (s, 1H). 91

428 0.28 (DMSO-d₆) δ 2.44-2.47 (m, 2H), 2.58 (t, J = 5.1 Hz, 2H), 3.14(d, J = 2.1 Hz, 2H), 3.19 (m, 2H), 3.68-3.70 (m, 2H), 3.80 (s, 3H), 3.82(s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.00 (td, J = 7.4, 0.9 Hz, 1H),7.09 (d, J = 7.6 Hz, 1H), 7.19 (dd, J = 7.4, 1.7 Hz, 1H), 7.39 (ddd, J =8.3, 7.4 Hz, 1.8 Hz, 1H), 7.76 (s, 1H), 9.52 (s, 1H). 92

414 0.44 (DMSO-d₆) δ 2.54 (br s, 4H), 3.14 (s, 2H), 3.65 (br s, 4H),3.82 (s, 3H), 5.95 (s, 2H), 6.82-6.88 (m, 2H), 6.91 (s, 1H), 7.12 (dd, J= 7.5, 1.7 Hz, 1H), 7.22 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.77 (s, 1H),9.54 (s, 1H), 9.83 (br s, 1H). 93

414 0.43 (DMSO-d₆) δ 2.55 (br. s, 4H), 3.15 (s, 2H), 3.65 (br s, 4H),3.83 (s, 3H), 5.95 (s, 2H), 6.75 (dd, J = 2.4, 1.5 Hz, 1H), 6.79 (dt, J= 7.5, 1.3 Hz, 1H), 6.83 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 6.91 (s, 1H),7.23 (t, J = 7.6 Hz, 1H), 7.77 (s, 1H), 9.53 (s, 1H), 9.76 (br s, 1H).94

399 1.51 (DMSO-d₆) δ 2.50-2.53 (m, 2H), 2.60- 2.62 (m, 2H), 3.14 (s,2H), 3.45 (t, J = 5.0 Hz, 2H), 3.70-3.72 (m, 2H), 3.81 (s, 3H), 5.93 (s,2H), 6.89 (s, 1H), 7.47 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.57 (dt, J =7.8, 1.1 Hz, 1H), 7.75 (s, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 8.57(ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 9.51 (s, 1H). 95

399 1.34 (DMSO-d₆) δ 2.55 (br s, 2H), 2.61 (br s, 2H), 3.16 (s, 2H),3.40 (br s, 2H), 3.71 (br s, 2H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.49 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.77 (s, 1H), 7.85 (dt, J =7.8, 1.9 Hz, 1H), 8.63 (dd, J = 2.3, 0.9 Hz, 1H), 8.65 (dd, J = 4.9, 1.7Hz, 1H), 9.52 (s, 1H). 96

399 1.44 (DMSO-d₆) δ 2.52 (m, 2H), 2.61- 2.64 (m, 2H), 3.16 (s, 2H),3.43 (br s, 2H), 3.71 (br s, 2H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.40-7.41 (m, 2H), 7.76 (s, 1H), 8.67-8.68 (m, 2H), 9.51 (s, 1H).97

416 <1 (DMSO-d₆) δ 2.50-2.61 (m, 3H), 3.13 (s, 2H), 3.18-3.74 (m, 5H),3.81 (s, 3H), 5.93 (s, 2H), 6.89 (s, 1H), 7.21-7.35 (m, 2H), 7.42-7.52(m, 1H), 7.75 (s, 1H), 7.93-8.03 (m, 1H), 9.51 (s, 1H). 98

402 1.08 (DMSO-d₆) δ 2.54-2.56 (m, 4H), 3.15 (s, 2H), 3.66 (m, 4H), 3.83(s, 3H), 3.85 (s, 3H), 5.95 (s, 2H), 6.92 (s, 1H), 7.67 (d, J = 0.7 Hz,1H), 7.78 (s, 1H), 8.06 (s, 1H), 9.54 (s, 1H). 99

442 0.60 (DMSO-d₆) δ 2.44-2.53 (m, 4H), 3.12 (s, 2H), 3.50-3.59 (m, 4H),3.62 (s, 2H), 3.76 (s, 3H) 3.82 (s, 3H), 5.95 (s, 2H), 6.83- 7.00 (m,3H), 7.03-7.28 (m, 2H), 7.77 (s, 1H), 9.52 (s, 1H). 100

428 0.43 (DMSO-d₆) δ 2.46 (m, 4H), 3.11 (s, 2H), 3.55 (m, 4H), 3.59 (s,2H), 3.81 (s, 3H), 5.95 (s, 2H), 6.51 (m, 1H), 6.70-6.77 (m, 1H), 6.80(dd, J = 8.5, 1.3 Hz, 1H), 6.91 (s, 1H), 7.04 (d, J = 7.1 Hz, 1H), 7.76(s, 1H), 8.31 (s, 1H), 9.51 (s, 1H). 282

454 0.038 (DMSO-d₆) δ 2.50-2.62 (m, 4H), 2.58 (s, 3H), 3.18 (s, 2H),3.31 (d, J = 0.6 Hz, 3H), 3.39 (br s, 2H), 3.77 (br s, 2H), 4.45 (s,2H), 6.14 (s, 2H), 7.36-7.42 (m, 4H), 7.62 (s, 1H), 8.33 (d, J = 0.5 Hz,1H), 12.69 (s, 1H). 283

455 0.125 (DMSO-d₆) δ 2.50-2.54 (m, 2H), 2.59 (s, 3H), 2.59-2.64 (m,2H), 3.19 (s, 2H), 3.37 (s, 3H), 3.50- 3.55 (m, 2H), 3.77-3.83 (m, 2H),4.51 (s, 2H), 6.14 (s, 2H), 7.48 (dd, J = 7.8, 0.7 Hz, 2H), 7.62 (s,1H), 7.94 (t, J = 7.8 Hz, 1H), 8.33 (s, 1H), 12.71 (s, 1H). 284

418 0.030 (DMSO-d₆) δ 2.54-2.61 (m, 2H), 2.59 (s, 3H), 2.62-2.69 (m,2H), 3.22 (s, 2H), 3.67-3.74 (m, 2H), 3.85-3.92 (m, 2H), 6.14 (s, 2H),7.63 (s, 1H), 8.34 (s, 1H), 9.60 (d, J = 0.5 Hz, 1H), 12.72 (s, 1H). 285

417 0.034 (DMSO-d₆) δ 2.52-2.64 (m, 4H), 2.58 (s, 3H), 3.19 (s, 2H),3.77- 3.84 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.19 (d, J = 2.0 Hz,1H), 8.34 (s, 1H), 9.17 (d, J = 2.0 Hz, 1H), 12.71 (s, 1H). 286

401 0.108 (DMSO-d₆) δ 2.54-2.62 (m, 4H), 2.58 (s, 3H), 3.19 (s, 2H),3.76 (br s, 2H), 4.02 (br s, 2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s,1H), 8.50-8.51 (m, 1H), 8.59- 8.60 (m, 1H), 12.71 (s, 1H). 287

430 0.23 (DMSO-d₆) 2.58 (m, 76H), 3.19 (s, 2H), 3.83 (br, 4H), 4.37-4.46(m, 2H), 5.38 (m, 1H), 6.14 (s, 2H), 6.43 (d, J = 3.4 Hz, 1H), 6.94 (d,J = 3.4 Hz, 1H), 7.63 (s, 1H), 8.34 (s, 1H), 12.72 (s, 1H). 288

444 0.065 (DMSO-d₆) δ δ 2.59 (m, 7H), 3.19 (br, 2H), 3.25-3.27 s, 3H),3.81 (br, 4H), 4.40 (s, 2H), 6.15 (s, 2H), 6.58 (d, J = 3.3 Hz, 1H),6.97 (d, J = 3.4 Hz, 1H), 7.63 (s, 1H), 8.34 (br, 1H), 12.72 (br, 1H).289

460 0.021 (DMSO-d₆) δ 2.54-2.62 (, 7H), 3.19 (s, 2H), 3.30 (d, J = 1.1Hz, 3H), 3.75-3.83 (m, 4H), 4.58 (s, 2H), 6.14 (d, J = 1.1 Hz, 2H),7.02-7.05 (m, 1H), 7.31 (dd, J = 3.7, 1.1 Hz, 1H), 7.62 (d, J = 1.1 Hz,1H), 8.33 (d, J = 1.1 Hz, 1H), 12.70 (s, 1H). 290

428 0.01 (DMSO-d₆) δ 1.94 (s, 3H), 2.23 (s, 3H), 2.55 (t, J = 5.0 Hz,4H), 2.59 (s, 3H), 3.18 (s, 2H), 3.80 (m, 4H), 6.14 (s, 2H), 6.81 (s,1H), 7.63 (s, 1H), 8.34 (s, 1H), 12.71 (s, 1H). 291

472 0.049 (DMSO-d₆) δ 1.16 (td, J = 7.5, 1.3 Hz, 3H), 2.54-2.61 (m, 7H),2.65-2.73 (m, 2H), 3.19 (s, 2H), 3.22 (d, J = 1.3 Hz, 3H), 3.81 (br s,4H), 4.23 (d, J = 1.2 Hz, 2H), 6.14 (d, J = 1.3 Hz, 2H), 6.91 (d, J =1.2 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 1.3 Hz, 1H), 12.71(s, 1H). 292

480 0.006 (DMSO-d₆) δ 2.52-2.57 (m, 4H), 2.59 (s, 3H), 3.18 (s, 2H),3.76 (br s, 4H), 5.42 (s, 2H), 6.14 (s, 2H), 6.25-6.30 (m, 1H), 6.51-6.53 (m, 1H), 6.95 (d, J = 3.4 Hz, 1H), 7.46 (dd, J = 1.8, 0.7 Hz, 1H),7.63 (s, 1H), 7.80 (dd, J = 2.3, 0.7 Hz, 1H), 8.34 (s, 1H), 12.70 (s,1H). 293

415 0.008 (DMSO-d₆) δ 2.29 (s, 3H), 2.53- 2.63 (m, 4H), 2.59 (s, 3H),3.20 (s, 2H), 3.69 (br s, 2H), 3.78 (br s, 2H), 6.14 (s, 2H), 6.82 (s,1H), 7.63 (s, 1H), 8.33 (s, 1H), 12.70 (s, 1H). 294

445 0.07 (DMSO-d₆) δ 2.53-2.66 (m, 7H), 3.20 (s, 2H), 3.3 (s, 3H),3.67-3.73 (m, 2H), 3.81 (s, 2H), 4.60 (d, J = 0.6 Hz, 2H), 6.14 (s, 2H),6.74-6.79 (m, 1H), 7.63 (s, 1H), 8.33 (s, 1H), 12.71 (s, 1H). 295

461 0.020 (DMSO-d₆) δ 2.52-2.61 (m, 4H), 2.59 (s, 3H), 3.19 (s, 2H),3.41 (s, 3H), 3.79 (br s, 4H), 4.73 (s, 2H), 6.14 (s, 2H), 7.62 (s, 1H),8.12 (d, J = 0.4 Hz, 1H), 8.34 (s, 1H), 12.71 (s, 1H). 296

445 0.053 (DMSO-d₆) δ 2.54-2.62 (m, 7H), 3.19 (s, 2H), 3.32 (d, J = 0.8Hz, 3H), 3.76 (br s, 2H), 4.02 (br s, 2H), 4.53 (d, J = 0.8 Hz, 2H),6.14 (s, 2H), 7.62 (d, J = 0.8 Hz, 1H), 8.33 (d, J = 0.8 Hz, 1H), 8.58(d, J = 0.8 Hz, 1H), 12.70 (s, 1H). 297

415 0.023 (DMSO-d₆) δ 2.45 (s, 3H), 2.56 (t, J = 5.0 Hz, 4H), 2.58 (s,3H), 3.18 (s, 2H), 3.74 (br s, 2H), 4.05 (br s, 2H), 6.14 (s, 2H), 7.62(s, 1H), 8.33 (d, J = 0.5 Hz, 1H), 8.42 (d, J = 0.5 Hz, 1H), 12.70 (s,1H). 298

415 0.091 (DMSO-d₆) δ 2.29 (s, 3H), 2.53- 2.58 (m, 4H), 2.58 (s, 3H),3.19 (s, 2H), 3.56-3.83 (m, 4H), 6.14 (s, 2H), 7.63 (s, 1H), 8.34 (s,1H), 9.16 (s, 1H), 12.70 (s, 1H). 299

415 0.058 (DMSO-d₆) δ 2.46 (d, J = 0.9 Hz, 3H), 2.54-2.59 (m, 7H), 3.18(s, 2H), 3.74 (br s, 2H), 3.94 (br s, 2H), 6.14 (d, J = 1.0 Hz, 2H),7.62 (d, J = 0.9 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H), 8.33 (d, J = 0.9 Hz,1H), 12.70 (s, 1H). 300

415 0.04 (DMSO-d₆) δ 2.45 (s, 3H), 2.53- 2.61 (m, 7H), 3.20 (s, 2H),3.64- 3.85 (m, 4H), 6.14 (s, 2H), 6.48 (dd, J = 1.4, 0.8 Hz, 1H), 7.62(s, 1H), 8.33 (s, 1H), 12.70 (s, 1H). 301

400 0.02 (DMSO-d₆) δ 2.56-2.65 (m, 7H), 3.19 (s, 2H), 3.80 (s, 2H), 4.61(s, 2H), 6.14 (s, 2H), 7.07 (dd, J = 1.6, 1.1 Hz, 1H), 7.25 (dd, J =2.4, 1.1 Hz, 1H), 7.63 (s, 1H), 8.34 (s, 1H), 12.72, s, 1H), 12.93 (s,1H). 302

400 0.8 (DMSO-d₆) δ 2.56 (m, 7H), 3.18 (s, 2H), 3.78 (br, 2H), 4.08 (br,2H), 6.14 (s, 2H), 6.58 (d, J = 2.2 Hz, 1H), 7.62 (s, 1H), 7.81 (s, 1H),8.34 (s, 1H), 12.71 (s, 1H). 303

401 0.06 (DMSO-d₆) δ 2.59 (m, 7H), 3.19 (s, 2H), 3.80 (m, 2H), 4.07 (m,2H), 6.14 (s, 2H), 7.63 (s, 1H), 8.34 (m, 2H), 12.72 (s, 1H). 304

401 0.08 (DMSO-d₆) δ 2.47-2.64 (m, 7H), 3.19 (d, J = 4.9 Hz, 2H),3.48-3.61 (m, 2H), 3.81 (m, 1H), 3.98 (m, 1H), 6.14 (s, 2H), 7.62 (d, J= 0.7 Hz, 1H), 8.34 (s, 1H), 12.70 (d, J = 12.0 Hz, 1H). 305

414 0.031 (DMSO-d₆) δ 2.55-2.62 (m, 4H), 2.58 (s, 3H), 3.19 (s, 2H),3.76 (s, 3H), 3.76-3.82 (m, 2H), 4.00-4.06 (m, 2H), 6.14 (s, 2H), 6.97(d, J = 1.1 Hz, 1H), 7.30 (d, J = 1.1 Hz, 1H), 7.62 (s, 1H), 8.34 (s,1H), 12.72 (s, 1H). 306

402 0.077 (DMSO-d₆) δ 2.15 (s, 1.5H), 2.18 (s, 1.5H), 2.59 (br s, 4H),3.15 (s, 2H), 3.69 (br s, 2H), 3.83 (s, 3H), 4.55 (br s, 2H), 5.95 (s,2H), 6.77 (s, 0.5H), 6.92 (s, 1H), 6.95 (s, 0.5H), 7.79 (s, 1H), 9.58(s, 1H), 12.62 (s, 0.5H), 12.69 (s, 0.5H). 307

414 0.09 (DMSO-d₆) δ 2.06 (s, 3H), 2.58 (m, 7H), 3.18 (s, 2H), 3.80 (m,4H), 6.14 (s, 2H), 7.59 (s, 1H), 7.62 (s, 1H), 8.34 (s, 1H), 12.71 (s,1H), 12.84 (s, 1H). 308

414 0.009 (DMSO-d₆) δ 2.16 (dd, J = 16.6, 0.9 Hz, 3H), 2.56-2.61 (m,7H), 3.18 (d, J = 1.3 Hz, 2H), 3.78 (br, 2H), 4.62 (br, 2H), 6.14 (s,2H), 6.76 (m, 0.5H), 6.95 (m, 0.5H), 7.63 (s, 1H), 8.34 (s, 1H), 12.72(s, 1H). 309

414 0.2 (DMSO-d₆) δ 2.27 (s, 3H), 2.53 (m, 4H), 2.59 (s, 3H), 3.17 (s,2H), 3.8-4.4 (br, 4H), 6.14 (s, 2H), 7.48 (s, 1H), 7.62 (s, 1H), 8.34(s, 1H), 12.20 (m, 1H), 12.71 (s, 1H). 310

441 0.8 (DMSO-d₆) δ 2.55 (m, 4H), 2.59 (s, 3H), 3.19 (s, 2H), 3.60 (m,4H), 6.14 (s, 2H), 6.88-6.97 (m, 1H), 7.19-7.26 (m, 2H), 7.42- 7.48 (m,2H), 7.63 (s, 1H), 8.35 (s, 1H), 8.55 (s, 1H), 12.68 (s, 1H). 311

394 0.082 (DMSO-d₆) δ 2.46-2.50 (m, 2H), 2.51-2.54 (m, 2H), 3.18 (s,2H), 3.28 (s, 3H), 3.47-3.54 (m, 2H), 3.54-3.61 (m, 2H), 3.84 (s, 3H),4.10 (s, 2H), 6.13 (s, 2H), 7.41 (s, 1H), 8.29 (s, 1H), 12.05 (s, 1H).312

408 0.157 (DMSO-d₆) δ 2.44-2.49 (m, , 2H), 2.51-2.55 (m, 2H), 2.58 (t, J= 6.6 Hz, 2H), 3.18 (s, 2H), 3.22 (s, 3H), 3.54 (t, J = 6.6 Hz, 2H),3.56-3.62 (m, 4H), 3.84 (s, 3H), 6.13 (s, 2H), 7.42 (s, 1H), 8.30 (s,1H), 12.05 (s, 1H). 313

418 0.06 (DMSO-d₆) 2.11-2.24 (m, 1H), 2.36-2.48 (m, 3H), 2.58 (m, 7H),3.19 (d, J = 1.6 Hz, 2H), 3.64 (m, 4H), 5.51 (m, 1H), 6.14 (s, 2H), 7.63(s, 1H), 8.33 (s, 1H), 12.68 (s, 1H). 314

404 0.06 (DMSO-d₆) δ 1.78-1.87 (m, 2H), 1.96-2.07 (m, 2H), 2.48- 2.53(m, 4H), 2.58 (s, 3H), 3.16 (s, 2H), 3.61-3.78 (m, 6H), 4.67 (dd, J =7.7, 5.6 Hz, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H), 12.68 (s,1H). 315

404 0.13 (DMSO-d₆) δ 1.77-1.88 (m, 2H), 1.94-2.07 (m, 2H), 2.48- 2.53(m, 4H), 2.58 (s, 3H), 3.16 (s, 2H), 3.61-3.80 (m, 6H), 4.67 (dd, J =7.6, 5.6 Hz, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H), 12.69 (s,1H). 316

418 0.08 (DMSO-d₆) δ 1.15 (d, J = 7.0 Hz, 3H), 1.78-1.87 (m, 2H), 1.93-2.06 (m, 2H), 2.45 (br. s, 2H), 2.58 (s, 3H), 3.37-3.40 (m, 2H),3.61-3.80 (m, 5H), 4.66 (dd, J = 7.6, 5.7 Hz, 1H), 6.13 (s, 2H), 7.61(s, 1H), 8.35 (s, 1H), 12.80 (s, 1H). 317

418 0.2 (DMSO-d₆) δ 1.15 (d, J = 7.0 Hz, 2H), 1.79-1.87 (m, 2H), 1.96-2.06 (m, 2H), 2.46 (br. s, 2H), 2.57 (s, 3H), 3.37-3.39 (m, 2H),3.61-3.80 (m, 5H), 4.66 (dd, J = 7.6, 5.6 Hz, 1H), 6.13 (m, 1H), 7.61(s, 1H), 8.35 (s, 1H), 12.80 (s, 1H). 318

418 0.06 (DMSO-d₆) δ 1.15 (d, J = 7.0 Hz, 3H), 1.79-1.87 (m, 2H), 1.97-2.06 (m, 2H), 2.45 (m, 4H), 2.58 (s, 3H), 3.37-3.38 (m, 1H), 3.61- 3.68(m, 4H), 3.73-3.78 (m, 2H), 4.66 (dd, J = 7.7, 5.6 Hz, 1H), 6.13 (s,2H), 7.61 (s, 1H), 8.35 (s, 1H), 12.81 (s, 1H). 319

432 1.0 (DMSO-d₆) δ 1.16 (s, 6H), 1.79- 1.85 (m, 2H), 1.95-2.05 (m, 2H),2.37-2.47 (m, 4H), 2.58 (s, 3H), 3.57-3.71 (m, 4H), 3.73- 3.80 (m, 2H),4.65 (dd, J = 7.7, 5.6 Hz, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 8.34 (s,1H), 12.84 (s, 1H). 320

448 1.6 (Methanol-d₄) δ 1.90-2.07 (m, 3H), 2.16-2.22 (m, 1H), 2.57 (s,3H), 2.67-2.70 (m, 2H), 2.79- 2.83 (m, 2H), 3.31 (s, 3H), 3.39- 3.41 (m,1H), 3.76-3.87 (m, 7H), 3.94 (q, J = 7.2 Hz, 1H), 4.73 (dd, J = 7.9, 5.8Hz, 1H), 6.05 (s, 2H), 7.48 (s, 1H), 8.33 (s, 1H). 321

417 1 (DMSO-d₆) δ 1.87-2.10 (m, 3H), 2.39 (s, 3H), 2.47-2.53 (m, 4H),2.55-2.61 (m, 4H), 2.75 (m, 2H), 2.93 (t, J = 8.9 Hz, 1H), 3.26- 3.40(m, 2H), 3.62 (m, 4H), 6.14 (s, 2H), 7.62 (s, 1H), 8.33 (s, 1H), 12.67(s, 1H). 322

418 0.07 (DMSO-d₆) δ 1.47 (m, , 21H), 1.81 (m, 2H), 2.00 (m, 2H), 2.36-2.48 (m, 4H), 2.58 (s, 3H), 2.66 (m, 1H), 3.16 (s, 2H), 3.49-3.64 (m,4H), 3.73 (m, 1H), 4.05- 4.17 (m, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34(s, 1H), 12.68 (s, 1H). 323

418 0.2 (DMSO-d₆) δ 1.48 (m, 1H), 2.00 (m, 1H), 2.34-2.49 (m, 6H), 2.57(s, 3H), 3.16 (s, 2H), 3.24 (dd, J = 8.3, 6.0 Hz, 1H), 3.51- 3.64 (m,6H), 3.71 (m, 1H), 3.82 (m, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s,1H), 12.67 (s, 1H). 324

414 0.08 (DMSO-d₆) δ 2.48 (m, , 4H), 2.56- 2.60 (s, 3H), 3.16 (s, 2H),3.57- 3.71 (m, 4H), 3.80 (s, 2H), 6.14 (d, J = 1.4 Hz, 2H), 6.22 (dt, J= 3.2, 0.8 Hz, 1H), 6.39 (dd, J = 3.1, 1.9 Hz, 1H), 7.56 (dd, J = 1.9,0.9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 8.33 (d, J = 0.7 Hz, 1H), 12.68(s, 1H). 325

468 0.045 (DMSO-d₆) δ 2.51-2.61 (m, 4H), 2.57 (s, 3H), 3.16 (s, 2H),3.31 (s, 3H), 3.48 (br s, 2H), 3.77 (br s, 2H), 4.25-4.29 (m, 2H),4.32-4.36 (m, 2H), 4.44 (s, 2H), 7.36-7.42 (m, 4H), 7.57 (s, 1H), 8.26(s, 1H), 12.39 (s, 1H). 326

425 0.04 327

425 0.07 (DMSO-d₆) 2.52 (m, 2H), 2.57 (s, 3H), 2.61 (m, 2H), 3.17 (s,2H), 3.38-3.47 (m, 2H), 3.79 (m, 2H), 4.30 (m, 4H), 7.37-7.46 (m, 2H),7.57 (s, 1H), 8.26 (s, 1H), 8.67 (d, J = 5.4 Hz, 2H), 12.38 (s, 1H). 328

415 0.06 2.56 (m, 7H), 3.15 (d, J = 5.7 Hz, 2H), 3.79 (m, 4H), 4.21-4.37(m, 4H), 7.56 (s, 1H), 8.25 (s, 1H), 8.64 (s, 1H), 12.40 (s, 1H). 329

415 0.05 330

414 0.09 331

428 0.2 (DMSO-d₆) 2.28 (s, 3H), 2.39- 2.58 (m, 7H), 3.15 (s, 2H), 3.34(br, 2H), 3.77 (br, 2H), 4.31 (m, 4H), 7.48 (s, 1H), 7.58 (d, J = 1.7Hz, 1H), 8.17 (s, H), 8.28 (d, J = 1.6 Hz, 1H), 12.41 (s, 1H). 332

428 0.2 (DMSO-d₆) 2.16 (dd, J = 16.7, 0.9 Hz, 3H), 2.56-2.60 (m, 7H),3.16 (d, J = 1.4 Hz, 2H), 3.78 (s, 2H), 4.24-4.38 (m, 4H), 4.62 (s, 2H),6.76 (s, 0.5H), 6.95 (s, 0.5H), 7.58 (d, J = 1.0 Hz, 1H), 8.27 (d, J =0.9 Hz, 1H), 12.42 (s, 1H), 12.6 (br, 1H) 333

428 0.08 (DMSO-d₆) 2.32 (dd, J = 1.0, 0.5 Hz, 3H), 2.57 (m, 7H), 3.17(s, 2H), 3.81 (br, 4H), 4.23-4.41 (m, 4H), 6.25 (dt, J = 3.3, 1.0 Hz,1H), 6.90 (dd, J = 3.3, 0.6 Hz, 1H), 7.58 (s, 1H), 8.27 (s, 1H), 12.42(s, 1H). 334

428 0.05 (DMSO-d₆) δ 2.42-2.49 (m, 4H), 2.57 (s, 3H), 3.14 (s, 2H),3.56- 3.68 (m, 4H), 3.80 (s, 2H), 4.23- 4.38 (m, 4H), 6.19-6.41 (m, 2H),7.54-7.60 (m, 2H), 8.26 (s, 1H), 12.38 (s, 1H). 335

431 0.05 (DMSO-d₆) 2.08-2.22 (m, 1H), 2.36-2.48 (m, 3H), 2.57 (m, 7H),3.13-3.19 (m, 2H), 3.47- 3.73 (m, 4H), 4.24-4.38 (m, 4H), 5.51 (m, 1H),7.58 (s, 1H), 8.26 (s, 1H), 12.38 (s, 1H). 336

362 0.05 (DMSO-d₆) δ 1.99 (s, 3H), 2.43 (m, 2H), 2.50 (m, 2H), 2.55 (s,3H), 3.12 (s, 2H), 3.56 (m, 4H), 4.25 (m, 2H), 4.32 (m, 2H), 7.55 (s,1H), 8.25 (s, 1H), 12.35 (s, 1H). 337

376 0.06 (DMSO-d₆) δ 1.15 (d, J = 7.0 Hz, 3H), 2.01 (s, 3H), 2.43 (m,4H), 2.57 (s, 3H), 3.31-3.37 (m, 1H), 3.58 (q, J = 5.3 Hz, 4H), 4.26-4.29 (m, 2H), 4.33-4.36 (m, 2H), 7.57 (s, 1H), 8.28 (s, 1H), 12.50 (s,1H). 338

392 0.06 339

436 0.08 340

418 0.09 (DMSO-d₆) 1.74-2.08 (m, 4H), 2.47 (m, 4H), 2.57 (s, 3H), 3.14(s, 2H), 3.60 (m, 2H), 3.64-3.85 (m, 4H), 4.22-4.39 (m, 4H), 4.67 (m,1H), 7.57 (s, 1H), 8.27 (s, 1H), 12.39 (s, 1H). 341

418 1.8 (DMSO-d₆) δ 1.78-1.87 (m, 2H), 1.97-2.07 (m, 2H), 2.46-2.53 (m,4H), 2.57 (s, 3H), 3.14 (s, 2H), 3.60-3.80 (m, 6H), 4.27 (dt, J = 3.9,2.5 Hz, 2H), 4.34 (dt, J = 4.2, 2.6 Hz, 2H), 4.67 (dd, J = 7.7, 5.7 Hz,1H), 7.57 (s, 1H), 8.27 (s, 1H), 12.38 (s, 1H). 342

418 0.07 (DMSO-d₆) δ 1.77-1.89 (m, 2H), 1.94-2.09 (m, 2H), 2.48- 2.53(m, 4H), 2.58 (s, 3H), 3.15 (s, 2H), 3.61-3.81 (m, 6H), 4.28 (dt, J =4.0, 2.6 Hz, 2H), 4.35 (dt, J = 4.2, 2.6 Hz, 2H), 4.68 (dd, J = 7.6, 5.6Hz, 1H), 7.58 (s, 1H), 8.27 (s, 1H), 12.39 (s, 1H). 343

432 0.03 344

432 0.05 345

431 >10 346

431 0.023 (DMSO-d₆) δ 2.60 (t, J = 5.0 Hz, 4H), 3.21 (s, 2H), 3.77 (brs, 2H), 3.85 (s, 3H), 4.08 (s, 3H), 4.15 (br s, 2H), 6.13 (s, 2H), 7.42(s, 1H), 8.30 (s, 1H), 8.49 (s, 1H), 12.10 (s, 1H). 347

460 0.083 (DMSO-d₆) δ 2.59 (t, J = 4.9 Hz, 4H), 3.21 (s, 2H), 3.26 (s,3H), 3.79 (br s, 4H), 3.85 (s, 3H), 4.40 (s, 2H), 6.13 (s, 2H), 6.58 (d,J = 3.4 Hz, 1H), 6.96 (d, J = 3.4 Hz, 1H), 7.42 (s, 1H), 8.30 (s, 1H),12.08 (s, 1H). 348

364 0.166 (DMSO-d₆) δ 2.01 (s, 3H), 2.43- 2.49 (m, 2H), 2.52-2.57 (m,2H), 3.18 (s, 2H), 3.51-3.60 (m, 4H), 3.84 (s, 3H), 6.12 (s, 2H), 7.41(s, 1H), 8.29 (s, 1H), 12.04 (s, 1H). 349

392 0.244 (DMSO-d₆) δ 0.89 (t, J = 7.4 Hz, 3H), 1.45-1.56 (m, 2H), 2.29(t, J = 7.4 Hz, 2H), 2.44-2.49 (m, 2H), 2.51-2.55 (m, 2H), 3.18 (s, 2H),3.54-3.61 (m, 4H), 3.84 (s, 3H), 6.13 (s, 2H), 7.42 (s, 1H), 8.29 (s,1H), 12.04 (s, 1H). 350

420 0.299 (DMSO-d₆) δ 1.74-1.91 (m, 2H), 1.92-2.09 (m, 2H), 2.46-2.50(m, 2H), 2.52-2.58 (m, 2H), 3.18 (d, J = 1.1 Hz, 2H), 3.55-3.67 (m, 4H),3.69-3.80 (m, 2H), 3.84 (d, J = 1.1 Hz, 3H), 4.64- 4.69 (m, 1H), 6.13(d, J = 1.1 Hz, 2H), 7.42 (d, J = 1.1 Hz, 1H), 8.29 (d, J = 1.1 Hz, 1H),12.05 (s, 1H). 351

434 0.439 (DMSO-d₆) δ 1.42-1.52 (m, 1H), 1.72-1.88 (m, 2H), 1.95- 2.05(m, 1H), 2.37-2.48 (m, 3H), 2.51-2.56 (m, 2H), 2.62- 2.70 (m, 1H), 3.18(s, 2H), 3.52- 3.62 (m, 5H), 3.69-3.76 (m, 1H), 3.84 (s, 3H), 4.05-4.13(m, 1H), 6.13 (s, 2H), 7.42 (s, 1H), 8.29 (s, 1H), 12.04 (s, 1H). 352

449 0.74 (DMSO-d₆) δ 2.36-2.43 (m, 4H), 2.44-2.49 (m, 2H), 2.53- 2.59(m, 2H), 3.17 (d, J = 9.0 Hz, 4H), 3.52-3.61 (m, 6H), 3.63- 3.71 (m,2H), 3.84 (s, 3H), 6.13 (s, 2H), 7.42 (s, 1H), 8.29 (s, 1H), 12.05 (s,1H). 353

374 2.1 (DMSO-d₆) δ 1.69-1.76 (m, 4H), 2.01 (s, 3H), 2.46 (t, J = 5.1Hz, 2H), 2.53 (t, J = 4.9 Hz, 2H), 2.67- 2.77 (m, 4H), 3.16 (s, 2H),3.52- 3.60 (m, 4H), 3.86 (s, 3H), 7.69 (s, 1H), 8.39 (s, 1H), 11.73 (s,1H). 354

388 1.9 355

332 2.5 356

442 0.156 (DMSO-d₆) δ 2.51-2.64 (m, 4H), 3.15 (s, 2H), 3.30 (s, 3H),3.35- 3.49 (m, 2H), 3.59-3.75 (m, 2H), 3.83 (s, 3H), 4.45 (s, 2H), 5.95(s, 2H), 6.91 (s, 1H), 7.29-7.36 (m, 2H), 7.37-7.47 (m, 2H), 7.77 (s,1H), 9.53 (s, 1H). 357

448 0.208 (DMSO-d₆) δ 2.55-2.63 (, 4H), 3.16 (s, 2H), 3.30 (d, J = 0.9Hz, 3H), 3.67-3.75 (m, 4H), 3.84 (d, J = 0.9 Hz, 3H), 4.58 (s, 2H), 5.95(d, J = 0.9 Hz, 2H), 6.91 (d, J = 0.9 Hz, 1H), 7.04 (dd, J = 3.6, 0.9Hz, 1H), 7.31 (dd, J = 3.7, 0.9 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 9.53(s, 1H). 358

442 0.148 (DMSO-d₆) δ 2.51-2.63 (m, 4H), 3.15 (s, 2H), 3.31 (s, 3H),3.43 (br s, 2H), 3.68 (br s, 2H), 3.83 (s, 3H), 4.45 (s, 2H), 5.95 (s,2H), 6.91 (s, 1H), 7.36-7.42 (m, 4H), 7.77 (s, 1H), 9.53 (s, 1H). 359

449 0.261 (DMSO-d₆) δ 2.58 (br s, 4H), 3.15 (s, 2H), 3.41 (s, 3H), 3.71(br s, 4H), 3.83 (s, 3H), 4.73 (s, 2H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77(s, 1H), 8.12 (s, 1H), 9.54 (s, 1H). 360

403 0.735 (DMSO-d₆) δ 2.60 (t, J = 5.0 Hz, 4H), 3.16 (s, 2H), 3.70 (brs, 2H), 3.83 (s, 3H), 4.08 (s, 3H), 4.09 (br s, 2H), 5.95 (s, 2H), 6.92(s, 1H), 7.78 (s, 1H), 8.49 (s, 1H), 9.56 (s, 1H). 361

433 0.546 (DMSO-d₆) δ 2.59 (t, J = 4.9 Hz, 4H), 3.16 (s, 2H), 3.33 (d, J= 1.7 Hz, 3H), 3.67 (br s, 2H), 3.83 (d, J = 1.4 Hz, 3H), 3.94 (br s,2H), 4.53 (d, J = 1.4 Hz, 2H), 5.95 (d, J = 1.4 Hz, 2H), 6.91 (d, J =1.4 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.7 Hz, 1H), 9.54(s, 1H). 362

403 0.567 (DMSO-d₆) δ 2.46 (d, J = 0.9 Hz, 3H), 2.53-2.60 (m, 7H), 3.19(d, J = 0.9 Hz, 2H), 3.74 (br s, 2H), 3.94 (br s, 2H), 6.14 (d, J = 0.7Hz, 2H), 7.62 (d, J = 0.9 Hz, 1H), 8.32 (d, J = 1.0 Hz, 1H), 8.34 (d, J= 0.9 Hz, 1H), 12.70 (s, 1H). 363

416 0.600 (DMSO-d₆) δ 2.17 (s, 3H), 2.51- 2.57 (m, 4H), 3.15 (s, 2H),3.56- 3.63 (m, 4H), 3.76 (s, 3H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.78 (s, 1H), 7.85 (s, 1H), 9.53 (s, 1H). 364

336 1.56 (DMSO-d₆) δ 2.01 (s, 3H), 2.44- 2.48 (m, 2H), 2.51-2.56 (m,2H), 3.13 (s, 2H), 3.43-3.54 (m, 4H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91(s, 1H), 7.78 (s, 1H), 9.53 (s, 1H). 365

421 2.64 (DMSO-d₆) δ 2.34-2.43 (m, 4H), 2.44-2.49 (m, 2H), 2.53- 2.58(m, 2H), 3.14 (dd, J = 9.8, 4.6 Hz, 4H), 3.43-3.66 (m, 8H), 3.82 (d, J =5.4 Hz, 3H), 5.95 (d, J = 5.4 Hz, 2H), 6.91 (d, J = 5.4 Hz, 1H), 7.78(d, J = 5.4 Hz, 1H), 9.53 (d, J = 4.4 Hz, 1H). 366

416 0.2 (DMSO-d₆) δ 2.56 (s, 4H), 3.15 (s, 2H), 3.54 (m, 4H), 3.83 (s,3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.42-7.55 (m, 2H), 7.77 (s, 1H),7.94-8.05 (m, 2H), 13.07 (br, 1H). 367

416 0.6 (DMSO-d₆) δ 2.55-2.67 (m, 4H), 3.15 (s, 2H), 3.36 (m, 2H), 3.67(m, 2H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.20-7.35 (m, 3H),7.44-7.60 (m, 1H), 7.77 (s, 1H), 9.53 (s, 1H). 368

428 0.6 (DMSO-d₆) δ 2.52-2.60 (m, 4H), 3.15 (s, 2H), 3.62 (br, 4H), 3.79(s, 3H), 3.82 (s, 3H), 3.83 (s, 2H), 5.95 (s, 2H), 6.91 (s, 1H),7.33-7.42 (m, 2H), 7.78 (s, 1H), 7.84-7.93 (m, 2H), 9.54 (s, 1H). 369

428 0.3 (DMSO-d₆) δ 2.57 (m, 4H), 3.15 (s, 2H), 3.40 (br, 2H), 3.56-3.74br, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.02(m, 1H), 7.18 (m, 1H), 7.42- 7.45 (m, 1H), 7.52 (m, 1H), 7.77 (s, 1H),9.52 (s, 1H). 370

412 0.4 (DMSO-d₆) δ 2.45 (m, 4H), 3.10 (s, 2H), 3.55 (m, 4H), 3.73 (s,2H), 3.79 (s, 3H), 5.59 (s, 2H), 6.90 (s, 1H), 7.27-7.34 (m, 5H), 7.76(s, 1H), 12.32 (s, 1H). 371

430 0.9 (DMSO-d₆) δ 2.42-2.48 (m, 4H), 3.11 (s, 2H), 3.49-3.59 (m, 4H),3.73 (s, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.22- 7.32 (m,4H), 7.76 (s, 1H), 12.37 (br, 1H) 372

428 0.4 (DMSO-d₆) δ 2.39-2.49 (m, 4H), 3.10 (s, 2H), 3.52 (m, 4H), 3.63(s, 2H), 3.79 (s, 3H), 5.95 (s, 2H), 6.56-6.68 (m, 3H), 6.90 (s, 1H),7.09 (t, J = 8.0 Hz, 1H), 8.14 (s, 1H), 9.49 (s, 1H). 373

428 0.7 (DMSO-d₆) δ 2.37-2.48 (m, 4H), 3.09 (s, 2H), 3.51 (m, 4H), 3.59(s, 2H), 3.79 (s, 3H), 5.95 (s, 2H), 6.64-6.73 (m, 2H), 6.90 (s, 1H),6.97-7.04 (m, 2H), 7.76 (s, 1H), 9.50 (s, 1H). 374

442 0.3 (DMSO-d₆) δ 2.37-2.48 (m, 4H), 3.10 (s, 2H), 3.54 (m, 4H), 3.70(s, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 5.95 (s, 2H), 6.74-6.83 (m, 3H),6.90 (s, 1H), 7.17-7.26 (m, 1H), 7.76 (s, 1H), 9.50 (s, 1H). 375

442 1 (DMSO-d₆) δ 2.45 (m, 4H), 3.10 (s, 2H), 3.55 (m, 4H), 3.65 (s,2H), 3.73 (s, 3H), 3.79 (s, 3H), 5.95 (s, 2H), 6.81-6.94 (m, 2H),7.10-7.19 (m, 2H), 7.76 (s, 1H), 9.49 (s, 1H). 376

430 0.2 (DMSO-d₆) δ 2.60 (m, 4H), 3.14 (s, 2H), 3.62 (m, 4H), 3.76 (s,2H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.09-7.19 (m, 2H),7.21-7.35 (m, 2H), 7.77 (s, 1H), 9.53 (s, 1H). 377

430 0.2 (DMSO-d₆) δ 2.47 (m, 4H), 3.12 (s, 2H), 3.55 (m, 4H), 3.77 (s,2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.01-7.07 (m, 1H), 7.08(s, 1H), 7.27-7.43 (m, 1H), 7.76 (s, 1H), 9.50 (s, 1H). 378

413 1.1 379

398 0.4 (DMSO-d₆) δ 2.55 (br, 4H), 3.15 (s, 2H), 3.67 (br, 4H), 3.83 (s,3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.31-7.55 (m, 5H), 7.77 (s, 1H), 9.53(s, 1H). 380

414 0.8 (DMSO-d₆) δ 2.55 (m, 4H), 3.14 (s, 2H), 3.56 (m, 4H), 3.83 (s,3H), 5.95 (s, 2H), 6.71-6.85 (m, 2H), 6.91 (s, 1H), 7.21-7.32 (m, 2H),7.78 (s, 1H), 9.54 (s, 1H), 9.86 (s, 1H). 381

430 5 382

423 0.4 (DMSO-d₆) δ 2.61 (m, 4H), 3.16 (s, 2H), 3.37 (m, 2H), 3.70 (m,2H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H),7.77 (s, 1H), 7.87-7.98 (m, 2H), 9.52 (s, 1H). 383

428 0.6 (DMSO-d₆) δ 2.55 (m, 4H), 3.15 (s, 2H), 3.36 (m, 2H), 3.67 (m,2H), 3.83 (s, 3H), 4.53 (s, 2H), 5.95 (s, 2H), 6.91 (s, 1H), 7.26 (m,1H), 7.35 (m, 1H), 7.37- 7.44 (m, 2H), 7.77 (s, 1H), 8.19 (s, 1H), 9.53(s, 1H). 384

416 0.2 (DMSO-d₆) δ 2.26 (s, 3H), 2.45 (s, 3H), 2.54 (m, 4H), 3.14 (s,2H), 3.56 (br, 4H), 3.83 (s, 3H), 5.95 (s, 2H), 6.10 (d, J = 1.3 Hz,1H), 6.91 (s, 1H), 7.77 (s, 1H), 12.38 (s, 1H). 385

388 0.7 (DMSO-d₆) δ 2.52-2.63 (m, 4H), 3.15 (s, 2H), 3.69 (br, 2H), 3.83(d, J = 3.5 Hz, 3H), 3.98 (br, 2H), 5.95 (s, 2H), 6.58 (d, J = 2.2 Hz,1H), 6.91 (d, J = 0.8 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.81 (s, 1H),8.02 (s, H), 9.54 (d, J = 19.2 Hz, 1H). 386

388 0.2 (DMSO-d₆) δ 2.53-2.60 (m, 4H), 3.15 (s, 2H), 3.64 (m, 4H), 3.83(s, 3H), 5.95 (s, 2H), 6.67 (dd, J = 1.9, 0.9 Hz, 1H), 6.92 (s, 1H),7.74-7.76 (m, 1H), 7.78 (s, 1H), 8.05 (dd, J = 1.6, 0.8 Hz, 1H), 9.53(s, 1H). 387

390 >10 388

389 2.6 (DMSO-d₆) δ 2.47 (m, 4H), 3.16 (d, J = 5.4 Hz, 2H), 3.44 (m,2H), 3.72 (m, 2H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77 (d, J= 1.1 Hz, 1H), 8.02 (s, 1H), 9.52 (br, 1H), 9.54 (br, 1H). 389

403 0.4 (DMSO-d₆) δ 2.46 (s, 3H), 2.52- 2.62 (m, 4H), 3.16 (s, 2H),3.56- 3.74 (m, 4H), 3.83 (s, 3H), 5.95 (s, 2H), 6.47 (t, J = 0.9 Hz,1H), 6.91 (s, 1H), 7.76 (s, 1H), 9.51 (s, 1H). 390

402 2.7 (DMSO-d₆) δ 2.06 (s, 3H), 2.56- (m, 4H), 3.15 (s, 2H), 3.64 (m,4H), 3.83 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.59 (s, 1H), 7.78 (s,1H), 9.55 (s, 1H), 12.85 (s, 1H). 391

402 0.2 (DMSO-d₆) δ 2.47-2.66 (m, 7H), 3.16 (d, J = 5.4 Hz, 2H), 3.44(m, 2H), 3.72 (m, 2H), 3.83 (d, J = 2.7 Hz, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.77 (d, J = 1.1 Hz, 1H), 8.02 (s, 1H), 9.52 (s, 1H), 9.54 (s, 1H)392

402 1.3 2.28 (s, 3H), 2.47 (m, 1H), 2.52- 2.61 (m, 3H), 3.14 (d, J = 8.1Hz, 2H), 3.44 (m, 2H), 3.69 (m, 1H), 3.78-3.89 (m, 3H), 4.28 (m, 1H),5.95 (s, 2H), 6.88-6.96 (m, 1H), 7.78 (dd, J = 10.3, 0.7 Hz, 1H), 8.02(s, 1H), 9.49-9.64 (m, 1H). 393

388 0.2 (DMSO-d₆) δ 2.61 (m, 4H), 3.15 (d, J = 2.2 Hz, 2H), 3.71 (m,2H), 3.83 (d, J = 5.2 Hz, 3H), 4.55 (m, 2H), 5.95 (s, 2H), 6.92 (d, J =2.5 Hz, 1H), 7.08 (d, J = 1.4 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.78(d, J = 7.2 Hz, 1H), 9.58 (s, 1H), 12.94 (s, 1H). 394

388 1.3 395

416 0.1 (DMSO-d₆) δ 1.91-1.96 (s, 3H), 2.21-2.26 (s, 3H), 2.54-2.61 (m,4H), 3.15 (s, 2H), 3.72, (m, 4H), 3.83 (s, 3H), 5.95 (s, 2H), 6.81 (d, J= 0.5 Hz, 1H), 6.92 (s, 1H), 7.78 (s, 1H), 9.54 (s, 1H). 396

432 0.1 (DMSO-d₆) δ 2.59 (m, 4H), 3.16 (s, 2H), 3.26 (s, 3H), 3.73 (m,4H), 3.83 (s, 3H), 4.40 (s, 2H), 5.95 (s, 2H), 6.58 (d, J = 3.3 Hz, 1H),6.92 (s, 1H), 6.96 (d, J = 3.4 Hz, 1H), 7.78 (s, 1H), 9.53 (s, 1H). 397

433 0.77 (DMSO-d₆) δ 2.52-2.59 (m, 4H), 3.17 (s, 2H), 3.32 (s, 3H),3.58- 3.76 (m, 4H), 3.83 (s, 3H), 4.60 (s, 2H), 5.95 (s, 2H), 6.75 (t, J= 0.6 Hz, 1H), 6.91 (s, 1H), 7.76 (s, 1H), 9.52 (s, 1H). 398

418 0.63 (DMSO-d₆) δ 2.56-2.62 (m, 4H), 3.16 (d, J = 4.9 Hz, 2H), 3.44(m, 1H), 3.74 (m, 3H), 3.83 (d, J = 5.4 Hz, 3H), 4.43 (dt, J = 5.9, 0.5Hz, 2H), 5.38 (t, J = 5.9 Hz, 1H), 5.95 (s, 2H), 6.43 (m, 1H), 6.91 (d,J = 1.2 Hz, 1H), 6.94 (d, J = 3.3 Hz, 1H), 7.78 (s, 1H), 9.54 (s, 1H).399

389 1.4 400

433 0.3 (DMSO-d₆) δ 2.60 (m, 4H), 3.17 (s, 2H), 3.33 (s, 3H), 3.44 (d, J= 7.3 Hz, 2H), 3.62 (m, 4H), 3.83 (s, 3H), 5.95 (d, J = 1.8 Hz, 2H),6.75 (s, 1H), 6.91 (d, J = 1.1 Hz, 1H), 7.76 (s, 1H), 9.51 (s, 1H). 401

402 0.13 (DMSO-d₆) δ 2.48 (m, 4H), 3.13 (s, 2H), 3.47-3.61 (m, 4H), 3.79(s, 2H), 3.82 (s, 3H), 5.95 (s, 2H), 6.22 (dd, J = 3.1, 0.9 Hz, 1H),6.39 (dd, J = 3.1, 1.8 Hz, 1H), 6.91 (s, 1H), 7.56 (dd, J = 1.9, 0.9 Hz,1H), 7.77 (s, 1H), 9.52 (s, 1H). 402

406 1.1 403

350 1.4 (DMSO-d₆) δ 1.14 (d, J = 6.9 Hz, 3H), 2.01 (s, 3H), 2.42-2.49(m, 4H), 3.36-3.39 (m, 1H), 3.48- 3.51 (m, 4H), 3.82 (s, 3H), 5.95 (s,2H), 6.91 (s, 1H), 7.77 (s, 1H), 9.71 (s, 1H). 404

390 0.3 (DMSO-d₆) δ 1.44-1.81 (m, 8H), 2.47-2.56 (m, 4H), 2.89- 3.06 (m,1H), 3.13 (s, 2H), 3.55 (m, 4H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.78 (s, 1H), 9.53 (s, 1H). 405

418 1 (DMSO-d₆) δ 0.81 (d, J = 7.1 Hz, 3H), 1.18-1.50 (m, 5H), 1.51-1.72 (m, 5H), 1.87-1.99 (m, 1H), 2.31-2.49 (m, 3H), 2.59 (s, 1H), 2.77(m, 1H), 3.13 (s, 2H), 3.37-3.73 (m, 4H), 3.82 (s, 3H), 5.95 (s, 2H),6.91 (s, 1H), 7.77 (s, 1H), 9.53 (s, 1H). 406

392 1.8 (DMSO-d₆) δ 1.91-2.10 (m, 2H), 2.48-2.54 (m, 4H), 3.14 (s, 2H),3.41-3.48 (m, 1H), 3.50- 3.62 (m, 4H), 3.62-3.74 (m, 3H), 3.82 (s, 3H),3.86 (t, J = 8.1 Hz, 1H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77 (s, 1H), 9.52(s, 1H). 407

405 >10 408

406 0.88 (DMSO-d₆) δ 1.47 (m, 1H), 1.72- 1.89 (m, 2H), 2.00 (m, 1H),2.36-2.48 (m, 3H), 2.53, (m, 4H), 2.66 (dd, J = 15.1, 6.5 Hz, 1H), 3.13(s, 2H), 3.52 (m, 4H), 3.58 (m, 1H), 3.73 (m, 1H), 3.82 (s, 3H), 4.09(p, J = 6.6 Hz, 1H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77 (s, 1H), 9.53 (s,1H). 409

420 0.5 (DMSO-d₆) δ 1.10-1.28 (m, 2H), 1.33-1.56 (m, 4H), 1.68 (dd, J =50.8, 12.1 Hz, 3H), 2.31 (dd, J = 15.1, 5.3 Hz, 2H), 2.46 (m, 2H), 2.57(m, 2H), 3.12 (s, 2H), 3.29 (m, 2H), 3.52 (m, 4H), 3.57-3.69 (m, 1H),3.79 (m, 1H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.77 (s, 1H),9.52 (s, 1H). 410

332 1.142 (DMSO-d₆) δ 1.94-2.04 (m, 5H), 2.47 (t, J = 5.1 Hz, 2H), 2.53(t, J = 4.8 Hz, 2H), 2.80 (dt, J = 14.9, 7.3 Hz, 4H), 3.14 (d, J = 1.2Hz, 2H), 3.46-3.53 (m, 4H), 3.84 (d, J = 1.2 Hz, 3H), 6.94 (s, 1H), 8.04(s, 1H), 9.59 (s, 1H). 411

432 0.17 (DMSO-d₆) δ 1.14 (d, J = 7.0 Hz, 3H), 1.76-1.84 (m, 2H), 1.98-2.06 (m, 2H), 2.44 (m, 4H), 2.57 (s, 3H), 3.34-3.40 (m, 2H), 3.60- 3.66(m, 3H), 3.72-3.78 (m, 2H), 4.26-4.28 (m, 2H), 4.33- 4.35 (m, 2H), 4.66(dd, J = 7.6, 5.6 Hz, 1H), 7.57 (s, 1H), 8.28 (s, 1H), 12.50 (s, 1H).412

432 0.17 (DMSO-d₆) δ 1.14 (d, J = 7.0 Hz, 3H), 1.79-1.87 (m, 2H), 1.97-2.06 (m, 2H), 2.45 (m, 4H), 2.57 (s, 3H), 3.35 (m, 1H), 3.54-3.80 (m,6H), 4.26-4.28 (m, 2H), 4.33-4.34 (m, 2H), 4.66 (dd, J = 7.6, 5.6 Hz,1H), 7.57 (s, 1H), 8.28 (s, 1H), 12.51 (s, 1H). 413

482 0.19 (DMSO-d₆) δ 1.16 (d, J = 7.0 Hz, 3H), 2.54 (br. s, 4H), 2.57(s, 3H), 3.30 (s, 3H), 3.38 (m, 1H), 3.48 (br. s, 2H), 3.78 (br. s, 2H),4.25- 4.28 (m, 2H), 4.32-4.38 (m, 2H), 4.44 (s, 2H), 7.39 (m, 4H), 7.57(s, 1H), 8.27 (s, 1H), 12.51 (s, 1H). 414

390 7.6Compounds with hT2R54 IC₅₀ of 104 or lower are considered especiallypotent.

EXAMPLE 7 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-benzylpiperazin-1-yl)acetamide(101)

To a mixture ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochloride (Example 1a) (76 mg, 0.2 mmol), TEA (40 mg, 0.4 mmol),and Cs₂CO₃ (76 mg, 0.4 mmol) in DMF (1 mL) was added(chloromethyl)benzene (25 mg, 0.2 mmol). The mixture was irradiated inthe microwave at 150° C. for 10 minutes, diluted with methanol (1 mL),filtered, and the filtrate was purified by reverse phase HPLC(water/acetonitrile gradient) to give 20 mg of the title compound. MS396 (M+H⁺).

Compounds in Table 3 were prepared in a similar manner as described inExample 7 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperazin-1-yl)acetamidedihydrochloride (Example 1a) and the corresponding commerciallyavailable electrophiles.

TABLE 3 Obs. Mol hT2R54 Ion; MS IC50 SID Structure (M + H)⁺ (uM) ¹H NMR(400 MHz) 101

396 1.06 (DMSO-d₆) δ 2.53 (m, 5H), 2.57 (s, 3H), 3.12 (s, 2H), 3.51 (s,2H), 6.13 (s, 2H), 7.24 (m, 1H), 7.32 (d, J = 4.4 Hz, 4H), 7.61 (s, 1H),8.14 (s, 1H), 8.31 (s, 1H), 12.54 (s, 1H). MS 396 (M+ H+). 102

414 0.5 103

414 0.5 104

414 0.6 105

444 0.09 (DMSO-d₆) δ 2.50-2.60 (m, 12H), 3.12 (s, 2H), 3.50 (s, 2H),3.77 (s, 3H), 6.13 (s, 2H), 6.93-7.09 (m, 2H), 7.13 (dd, J = 9.5, 3.2Hz, 1H), 7.60 (s, 1H), 8.32 (s, 1H), 12.55 (s, 1H). 106

397 0.3 107

453 4.18 108

439 1.76 415

390 1.3 416

378 4Compounds with hT2R54 IC₅₀ of 1 μM or lower are considered especiallypotent.

EXAMPLE 8 Synthesis ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-morpholinoacetamide (109)

A solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromoacetamide(Example 1c) (2.5 g, 8.56 mmol) and morpholine (2.3 mL, 25.7 mmol) inacetonitrile (100 mL) was heated to 90° C. and stirred for 1 hour. Themixture was cooled to room temperature and concentrated under vacuum.The residue was stirred in a mixture of EtOAc (15 mL) and water (20 mL)for about 30 min, the solid product collected by filtration andrecrystallized from Et0H/H₂O to give the title compound (2.2 g, 84%yield) as a light brown solid. MS (M+H⁺) 307.

EXAMPLE 9 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-morpholinopropanamide (110)

To a solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromopropanamide(Example 9a) (55 mg, 0.175 mmol) in ACN was added morpholine (45 uL,0.525 mmol). The solution was heated at 90° C. for 2 hours andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (0-50% EtOAc/Hexanes gradient) to afford the titlecompound as a white solid (48.9 mg, 87% yield). MS 321 (M+H⁺).

EXAMPLE 9a N-(6-Acelylbenzok[d][1,3]dioxol-5-yl)-2-bromopropanamide

Prepared in a similar manner as in Example 1c from1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (185 mg, 1.033 mmol),TEA (288 uL, 2.065 mmol), and 2-bromopropionyl chloride (114 uL, 1.136mmol) to afford the title compound as an orange solid (282 mg, 87%yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.78 (d, J=6.4 Hz, 3H), 2.59 (s,3H), 4.84 (q, J=6.8 Hz, 1H), 6.16 (s, 2H), 7.63 (s, 1H), 8.06 (s, 1H),12.25 (s, 1H). MS 314 (M+H⁺).

EXAMPLE 10 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-methyl-2-morpholinopropanamide(111)

Prepared in a similar manner as in Example 9 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-bromo-2-methylpropanamide(Example 10a) (60 mg, 0.183 mmol) and morpholine (47 uL, 0.549 mmol) toafford the title compound as a white solid (13.2 mg, 22% yield). MS 335(M+H⁺).

EXAMPLE 10aN-(6-Acelylbenzo[d][1,3]dioxol-5-yl)-2-bromo-2-methylpropanamide

Prepared in a similar manner as in Example 1c from1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (250 mg, 1.40 mmol), TEA(389 uL, 2.79 mmol), and 2-bromo-2-methylpropanoyl chloride (285 mg,1.54 mmol) to afford the title compound as a yellow solid (272 mg, 59%yield). MS 329 (M+H⁺).

EXAMPLE 11 Synthesis of Ethyl(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-L-prolinate(112)

Prepared in a similar manner as in Example 1b fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (84mg, 0.280 mmol), L-proline ethyl ester HCl salt (55 mg, 0.308 mmol), andK₂CO₃ (116 mg, 0.840 mmol) in dry DMF (3 mL) at room temperature toafford the title compound as an orange powder (47.1 mg, 46% yield). MS363 (M+H⁺).

EXAMPLE 12 Synthesis of Ethyl1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-2-carboxylate(113)

Prepared in a similar manner as in Example 1b fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (75mg, 0.250 mmol) and ethyl pipecolinate HCl salt (53 mg, 0.275 mmol) toafford the title compound as an off-white solid (55.8 mg, 59% yield). MS377 (M+H⁺).

EXAMPLE 13 Synthesis of Ethyl1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethl)pyrrolidine-3-carboxylate(114)

Prepared in a similar manner as in Example 1b fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (120mg, 0.400 mmol) and ethyl pyrrolidine-3-carboxylate HCl salt (79 mg,0.440 mmol) to afford the title compound as an orange solid (14.5 mg,10% yield). MS 363 (M+H⁺).

EXAMPLE 14 Synthesis of Ethyl1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylate(115)

Prepared in a similar manner as in Example 1b fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (77mg, 0.257 mmol) and ethyl nipecotate (44 uL, 0.283 mmol) to afford thetitle compound as a yellowish solid (62.8 mg, 65% yield). MS 377 (M+H+).Alternatively, the title was synthesized in a similar manner as inExample 1b from N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide(Example 14a) (5.0 g, 20.0 mmol) and ethyl nipecotate (3.5 g, 22.0 mmol)to afford the title compound as a whitish solid (5.3 g, 70% yield). MS377 (M+H⁺).

EXAMPLE 14a N-(6-Acelylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide

Prepared in a similar manner as in Example 1c from1-(6-aminobenzo[d][1,3]-dioxol-5-yl)ethan-1-one (3.6 g, 20 mmol) andacetyl chloride, (2.4 mL, 30 mmol), and TEA (4.1 mL, 30 mmol) to yieldthe desired product 5.6 g (quantitative yield). ¹H NMR (400 MHz,DMSO-d6) δ 2.58 (s, 3H), 4.42 (s, 2H), 6.16 (s, 2H), 7.63 (s, 1H), 8.13(s, 1H), 12.45 (s, 1H). MS 256 (M+H⁺).

EXAMPLE 15 Synthesis of Ethyl1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-4-carboxylate(116)

Prepared in a similar manner as in Example 1b fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-bromoacetamide (Example 1c) (75mg, 0.250 mmol) and ethyl piperidine-4-carboxylate HCl salt (53 mg,0.275 mmol) to afford the title compound as an orange solid (10.9 mg,12% yield). MS 377 (M+H⁺).

EXAMPLE 16 Synthesis of Ethyl1-(2-((6-Methoxybenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylate(117)

Prepared in a similar manner as in Example 9 from2-chloro-N-(6-methoxybenzo-[d][1,3]dioxol-5-yl)cetamide (Example 16a)(100 mg, 0.4 mmol) and ethyl piperidine-3-carboxylate (63 mg, 0.4 mmol)to give 55 mg (30% yield) of the title compound as an off white gel. MS365 (M+H⁺).

EXAMPLE 16a 2-Chloro-N-(6-methoxybenzo[d][1,3]dioxol-5-yl)acetamide

Prepared in a similar manner as in Example 1c from6-methoxybenzo[d][1,3]-dioxol-5-amine (84 mg, 0.5 mmol) and acetylchloride (56 mg, 0.5 mmol) to yield the desired product as a greyishsolid (100 mg, 82% yield). MS 244 (M+H⁺).

EXAMPLE 17 Synthesis of Ethyl1-(2-((7-Acetyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoethyl)piperidine-3-carboxylate(118)

Prepared in a similar manner as in Example 9 fromN-(7-acetyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide(Example 17a) (200 mg, 0.64 mmol) and ethyl piperidine-3-carboxylate(148 μL, 0.96 mmol) to give the desired product as a yellowish oil (75mg, 30% yield). MS 391 (M+H⁺).

EXAMPLE 17aN-(7-Acelyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-chloroacetamide

Prepared in similar manner as in Example 1c from1-(7-amino-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (11 g, 56.94mmol) and 2-bromoacetyl chloride (7.08 mL, 85.40 mmol) to yield thedesired product as a brown solid (17.8 g, 99% yield). MS 315 (M+H⁺).

Compounds in Table 4 were prepared in a similar manner as in Example 1band/or Example 9 from the corresponding 2-chloro- and 2-bromo-acetamidessynthesized as described herein and commercially available aminenucleophiles.

TABLE 4 Obs Mol Ion hT2R54 MS; IC50 SID Structure (M + H⁺) (uM) ¹H NMR(400 MHz) 109

307      0.588 (DMSO-d₆) δ 2.48 (m, 4H), 2.56 (s, 3H), 3.11 (s, 2H),3.71 (t, J = 4.4 Hz, 4H), 6.11 (s, 2H), 7.59 (s, 1H), 8.30 (s, 1H),12.62 (s, 1H). 110

321      0.359 (DMSO-d₆) δ 1.18 (d, J = 7.2 Hz, 3H), 2.47 (m, 4H), 2.58(s, 3H), 3.25 (q, J = 7.2 Hz, 1H), 3.73 (t, J = 4.4 Hz, 4H), 6.13 (s,2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.74 (s, 1H). 111

335      0.207 (DMSO-d₆) δ 1.16 (s, 6H), 2.44 (t, J = 4.4 Hz, 4H), 2.58(s, 3H), 3.71 (t, J = 4.4 Hz, 4H), 6.12 (s, 2H), 7.60 (s, 1H), 8.32 (s,1H), 12.81 (s, 1H). 112

363      0.206 (DMSO-d₆) δ 1.09 (t, J = 6.8 Hz, 3H), 1.87-1.99 (m, 3H),2.18- 2.19 (m, 1H), 2.55 (s, 3H), 2.66- 2.67 (m, 1H), 3.03-3.06 (m, 1H),3.50-3.65 (m, 3H), 3.97- 4.05 (m, 2H), 6.14 (s, 2H), 7.60 (s, 1H), 8.31(s, 1H), 12.59 (s, 1H). 113

377      0.078 (DMSO-d₆) δ 1.17 (t, J = 7.2 Hz, 3H), 1.29-1.35 (m, 1H),1.52- 1.72 (m, 3H), 1.93-2.07 (m, 2H), 2.58 (s, 3H), 2.67 (m, 2H), 3.26(s, 2H), 3.54 (t, J = 4.8 Hz, 1H), 4.04-4.14 (m, 2H), 6.14 (s, 2H), 7.62(s, 1H), 8.36 (s, 1H), 12.66 (s, 1H). 114

363      0.061 (DMSO-d₆) δ 1.18 (t, J = 7.2 Hz, 3H), 2.05-2.14 (m, 2H),2.55 (s, 3H), 2.60-2.62 (m, 1H), 2.73- 2.77 (m, 2H), 2.97 (t, J = 8.4Hz, 1H), 3.09-3.15 (m, 1H), 3.28 (s, 2H), 4.07 (q, J = 7.2 Hz, 2H), 6.14(s, 2H), 7.60 (s, 1H), 8.30 (s, 1H), 12.53 (s, 1H). 115

377      0.009 (DMSO-d₆) δ 1.15 (t, J = 7.2 Hz, 3H), 1.31-1.41 (m, 1H),1.67- 1.74 (m, 2H), 1.91-1.94 (m, 1H), 2.16 (td, J = 10.8, 3.9 Hz, 1H),2.29 (t, J = 10.8 Hz, 1H), 2.70- 2.78 (m, 2H), 2.92 (d, J = 11.6 Hz,1H), 3.14 (d, J = 4.0 Hz, 2H), 4.01-4.07 (m, 2H), 6.14 (s, 2H), 7.61 (s,1H), 8.33 (s, 1H), 12.57 (s, 1H). 116

377      0.103 (DMSO-d₆) δ 1.19 (t, J = 7.2 Hz, 3H), 1.81-1.86 (m, 4H),2.19- 2.25 (m, 2H), 2.32-2.36 (m, 1H), 2.57 (s, 3H), 2.77-2.80 (m, 2H),3.09 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 6.13 (s, 2H), 7.61 (s, 1H), 8.33(s, 1H), 12.56 (s, 1H). 117

365      0.188 (DMSO-d₆) δ 1.14 (t, J = 7.1 Hz, 3H), 1.40-1.60 (m, 2H),1.63- 1.73 (m, 1H), 1.73-1.85 (m, 1H), 2.21-2.31 (m, 1H), 2.54- 2.66 (m,1H), 2.83-2.92 (m, 1H), 3.09 (s, 2H), 3.81 (s, 3H), 4.06 (q, J = 7.1 Hz,2H), 5.94 (s, 2H), 6.90 (s, 1H), 7.78 (s, 1H), 9.49 (s, 1H). 118

391      0.024 ¹H NMR (400 MHz, DMSO-d₆) δ 1.13-1.19 (m, 4H), 1.33-1.38(m, 1H), 1.67-1.70 (m, 2H), 1.90-2.08 (m, 1H), 2.13-2.19 (m, 1H), 2.28(t, J = 10.8 Hz, 1H), 2.56 (s, 3H), 2.69-2.79 (m, 1H), 2.91-2.95 (dd, J= 11.1, 3.7 Hz, 1H), 3.12 (d, J = 2.4 Hz, 2H), 4.00-4.07 (m, 2H),4.22-4.38 (m, 4H), 7.56 (s, 1H), 8.26 (s, 1H), 12.27 (s, 1H). 119

335      0.246 (DMSO-d₆) δ 1.05 (d, J = 6.3 Hz, 5H), 1.88 (dd, J = 11.3,10.1 Hz, 2H), 2.57 (s, 3H), 2.73 (d, J = 10.4 Hz, 2H), 3.10 (s, 2H),3.85 (m, 2H), 6.13 (s, 2H), 7.60 (s, 1H), 8.33 (s, 1H), 12.63 (s, 1H).120

321    <0.01 (DMSO-d₆) δ 1.55-1.70 (m, 2H), 1.70-1.84 (m, 2H), 2.23 (td,J = 11.7, 10.6, 2.9 Hz, 2H), 2.57 (s, 3H), 2.65-2.75 (m, 2H), 3.07 (s,2H), 3.52 (br-s, 1H), 4.61 (br-s, 1H), 6.13 (s, 2H), 7.60 (s, 1H), 8.33(s, 1H), 12.58 (s, 1H). 121

335      0.065 (DMSO-d₆) δ 1.67 (ddt, J = 13.4, 9.0, 4.5 Hz, 2H),1.86-1.93 (m, 2H), 2.23-2.34 (m, 2H), 2.57 (s, 3H), 2.63-2.76 (m, 2H),3.09 (s, 2H), 3.19-3.24 (m, 1H), 3.24 (s, 3H), 6.13 (s, 2H), 7.61 (s,1H), 8.34 (s, 1H), 12.61 (s, 1H). 122

321    <0.02 123

335      0.002 (DMSO-d₆) δ 1.03 (qd, J = 11.8, 5.2 Hz, 1H), 1.61-1.76(m, 2H), 1.92 (t, J = 10.0 Hz, 1H), 2.05 (td, J = 11.0, 4.1 Hz, 2H),2.57 (s, 3H), 2.67-2.73 (m, 1H), 3.00- 3.06 (m, 1H), 3.13 (d, J = 1.1Hz, 2H), 3.24 (s, 3H), 3.46 (tt, J = 9.5, 4.2 Hz, 1H), 6.13 (s, 2H),7.60 (s, 1H), 8.32 (s, 1H), 12.51 (s, 1H). 124

362      2.143 (DMSO-d₆) δ 1.14 (s, 6H), 1.60 (q, J = 10.0, 9.5 Hz, 2H),1.87 (d, J = 12.2 Hz, 2H), 2.22 (t, J = 10.4 Hz, 2H), 2.57 (s, 3H),2.58- 2.69 (m, 2H), 3.14-3.25 (m, 4H), 6.12 (s, 2H), 7.59 (s, 1H), 8.34(s, 1H), 12.77 (s, 1H). 125

363      0.100 ¹H NMR (400 MHz, DMSO-d₆) δ 1.81-1.86 (m, 4H), 2.19-2.25(m, 2H), 2.33-2.41 (m, 1H), 2.57 (s, 3H), 2.77 (m, 2H), 3.09 (s, 2H),3.62 (s, 3H), 6.13 (s, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.56 (s, 1H).126

377      0.154 127

379      0.013 (DMSO-d₆) δ 1.17 (t, J = 7.1 Hz, 3H), 1.20-1.25 (m, 1H),2.37- 2.44 (m, 1H), 2.53-2.64 (m, 1H), 2.57 (s, 3H), 2.83-2.94 (m, 1H),3.19 (d, J = 2.4 Hz, 2H), 3.76 (ddd, J = 11.5, 9.0, 2.7 Hz, 1H), 3.95(dt, J = 11.3, 3.4 Hz, 1H), 4.11 (qd, J = 7.1, 4.4 Hz, 2H), 4.38 (dd, J= 8.5, 3.0 Hz, 1H), 6.14 (s, 2H), 7.61 (s, 1H), 8.30 (s, 1H), 12.60 (s,1H). 128

379      0.079 (DMSO-d₆, rotamers) δ 1.13- 1.29 (m, 3H), 2.43-2.50 (m,1H), 2.53-2.62 (m, 3H), 3.02- 3.12 (m, 1H), 3.30-3.52 (m, 2H), 3.61-3.66(m, 1H), 3.70- 3.90 (m, 2H), 3.91-4.09 (m, 2H), 4.09-4.18 (m, 2H), 6.14(two s, 2H), 7.63 (two s, 1H), 8.36 (two s, 1H), 12.71 (br. s, 1H). 129

406    <1 130

333      0.312 (DMSO-d₆) δ 0.99-1.13 (m, 1H), 1.13-1.29 (m, 4H), 1.57(br d, J = 12.4 Hz, 1H), 1.68- 1.80 (m, 2H), 1.82-1.91 (m, 2H), 2.27 (s,3H), 2.38-2.47 (m, 1H), 2.55 (s, 3H), 3.14 (s, 2H), 6.13 (s, 2H), 7.59(s, 1H), 8.34 (s, 1H), 12.68 (s, 1H). 131

323      2.0 132

323      0.659 (DMSO-d₆) δ 2.45 (s, 3H), 2.56 (s, 3H), 3.37 (s, 2H),3.56 (s, 2H), 3.63 (s, 3H), 6.14 (s, 2H), 7.60 (s, 1H), 8.29 (s, 1H),12.58 (s, 1H). 133

351      0.113 (DMSO-d₆) δ 1.14 (t, J = 7.1 Hz, 3H), 2.28 (s, 3H),2.52-2.63 (m, 5H), 2.74 (t, J = 7.2 Hz, 2H), 3.15 (s, 2H), 4.02 (q, J =7.1 Hz, 2H), 6.13 (s, 2H), 7.60 (s, 1H), 8.30 (s, 1H), 12.51 (s, 1H).134

350      0.96 (DMSO-d6) δ 2.30 (s, 3H), 2.56 (s, 3H), 2.56-2.62 (m, 2H),2.64- 2.73 (m, 2H), 2.77 (s, 3H), 2.96 (s, 3H), 3.16 (s, 2H), 6.13 (s,2H), 7.59 (s, 1H), 8.30 (s, 1H), 12.53 (s, 1H). 135

350      0.50 (DMSO-d₆) δ 0.97 (t, J = 7.2 Hz, 3H), 2.28 (s, 3H), 2.32(dd, J = 8.3, 6.8 Hz, 2H), 2.56 (s, 3H), 2.70 (dd, J = 8.5, 6.7 Hz, 2H),3.02 (qd, J = 7.2, 5.4 Hz, 2H), 3.13 (s, 2H), 6.13 (s, 2H), 7.60 (s,1H), 7.83 (t, J = 4.9 Hz, 1H), 8.30 (s, 1H), 12.51 (s, 1H). 136

365      0.179 (DMSO-d₆) δ 1.02 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1Hz, 3H), 2.51-2.61 (m, 7H), 2.81 (t, J = 7.2 Hz, 2H), 3.18 (s, 2H), 3.98(q, J = 7.1 Hz, 2H), 6.13 (s, 2H), 7.59 (s, 1H), 8.33 (s, 1H), 12.53 (s,1H). 137

405      2.826 (DMSO-d₆) δ 1.05 (t, J = 7.1 Hz, 3H), 1.11-1.30 (m, 3H),1.33- 1.48 (m, 1H), 1.60 (d, J = 11.8 Hz, 1H), 1.68-1.86 (m, 2H), 1.91(d, J = 6.6 Hz, 1H), 2.29 (s, 3H), 2.46 (dd, J = 11.3, 3.6 Hz, 1H), 2.54(s, 3H), 2.75 (dt, J = 11.1, 5.5 Hz, 1H), 2.99 (d, J = 17.0 Hz, 1H),3.37 (d, J = 17.0 Hz, 1H), 3.89 (m, 2H), 6.13 (s, 2H), 7.58 (s, 1H),8.25 (s, 1H), 12.21 (s, 1H). 138

434      0.15 (DMSO-d₆) δ 0.70-0.90 (m, 1H), 1.18-1.52 (m, 11H), 1.64-1.76 (m, 1H), 1.92 (br d, J = 12.1 Hz, 1H), 2.32 (s, 3H), 2.37- 2.50 (m,1H), 2.56 (s, 3H), 2.59- 2.86 (m, 1H), 3.15-3.29 (m, 2H), 3.79 (br d, J= 13.0 Hz, 1H), 4.07 (br d, J = 12.4 Hz, 1H), 6.13 (s, 2H), 7.60 (s,1H), 8.34 (s, 1H), 12.69 (s, 1H). 139

420      0.176 (DMSO-d₆) δ 1.13-1.25 (m, 2H), 1.38 (s, 9H), 1.77-1.86(m, 2H), 2.55 (s, 4H), 2.62-2.70 (m, 1H), 2.77 (br-s, 2H), 3.29 (d, J =5.8 Hz, 2H), 3.84 (d, J = 13.2 Hz, 2H), 6.13 (s, 2H), 7.59 (s, 1H), 8.36(s, 1H), 12.66 (s, 1H). 140

434      0.433 (DMSO-d₆) δ 1.27-1.44 (m, 2H), 1.39 (s, 9H), 1.80 (d, J =12.4 Hz, 2H), 2.27 (s, 3H), 2.55 (s, 3H), 2.57-2.76 (m, 3H), 3.17 (s,2H), 3.98 (d, J = 13.2 Hz, 2H), 6.13 (s, 2H), 7.60 (s, 1H), 8.33 (s,1H), 12.68 (s, 1H). 141

405      0.168 (DMSO-d₆) δ 1.07-1.60 (m, 8H), 1.63-1.76 (m, 2H), 1.85-1.99 (m, 1H), 2.02-2.17 (m, 2H), 2.21-2.30 (m, 3H), 2.40- 2.60 (m, 5H),3.07-3.16 (m, 2H), 4.00-4.11 (m, 2H), 6.13 (s, 2H), 7.59 (s, 1H), 8.33(s, 1H), 12.66 (s, 1H). 142

339      0.23 (DMSO-d₆) δ 1.14 (t, J = 7.0 Hz, 3H), 2.28 (s, 3H),2.50-2.57 (m, 2H), 2.73 (t, J = 7.0 Hz, 2H), 3.11 (s, 2H), 3.78 (d, J =0.9 Hz, 3H), 3.96-4.11 (m, 2H), 5.94 (s, 2H), 6.89 (d, J = 0.8 Hz, 1H),7.78 (d, J = 0.8 Hz, 1H), 9.28 (s, 1H). 143

295      0.142 (DMSO-d₆) δ 2.50-2.55 (m, 4H), 3.10 (s, 2H), 3.65 (t, J =4.6 Hz, 4H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.79 (s, 1H),9.56 (s, 1H). 144

309    <2 145

323      0.575 (DMSO-d₆) δ 1.09-1.29 (m, 1H), 1.41-1.53 (m, 1H), 1.68-1.77 (m, 1H), 1.85-1.99 (m, 1H), 2.04-2.28 (m, 2H), 2.58- 2.67 (m, 1H),2.92 (br d, J = 11.2 Hz, 1H), 3.08 (s, 2H), 3.22-3.31 (m, 4H), 3.82 (s,3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.81 (s, 1H), 9.54 (s, 1H). 146

309    <2 (DMSO-d₆) δ 1.40-1.52 (m, 2H), 1.72-1.81 (m, 2H), 2.20- 2.33(m, 2H), 2.67-2.78 (m, 2H), 3.04 (s, 2H), 3.45-3.56 (m, 1H), 3.82 (s,3H), 4.63 (d, J = 4.2 Hz, 1H), 5.95 (s, 2H), 6.91 (s, 1H), 7.82 (s, 1H),9.63 (s, 1H). 147

323      0.448 (DMSO-d₆) δ 1.40-1.59 (m, 2H), 1.87-1.92 (m, 2H), 2.25-2.39 (m, 2H), 2.64-2.78 (m, 2H), 3.06 (s, 2H), 3.18-3.27 (m, 4H), 3.81(s, 3H), 5.95 (s, 2H), 6.91 (s, 1H), 7.81 (s, 1H), 9.59 (s, 1H). 148

394    <2 149

359      0.885 150

327      0.393 151

383      0.152 152

321      0.63 ¹H NMR (400 MHz, CDCl₃) δ2.57 (s, 3H), 6.61 (m, 4H), 2.27(s, 2H), 3.89 (m, 4H), 4.27 (m, 2H), 4.33 (m, 2H), 7.40 (s, 1H), 8.40(s, 1H), 12.49 (br s, 1H). 153

391      0.024 ¹H NMR (400 MHz, DMSO-d₆) δ 1.19 (t, J = 7.2 Hz, 3H),1.78- 1.86 (m, 4H), 2.18-2.24 (m, 2H), 2.32-2.35 (m, 1H), 2.56 (s, 3H),2.76 (m, 2H), 3.07 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 4.26-4.35 (m, 4H),7.56 (s, 1H), 8.26 (s, 1H), 12.26 (s, 1H). 417

305      0.439 (DMSO-d₆) δ 1.37-1.49 (m, 2H), 1.61-1.69 (m, 4H),2.39-2.47 (m, 4H), 2.57 (s, 3H), 3.05 (s, 2H), 6.13 (s, 2H), 7.60 (s,1H), 8.34 (s, 1H), 12.59 (s, 1H). 418

319      0.183 (DMSO-d₆) δ 0.93 (d, J = 5.8 Hz, 3H), 1.30-1.50 (m, 3H),1.54-1.62 (m, 2H), 2.07-2.17 (m, 2H), 2.56 (s, 3H), 2.73-2.81 (m, 2H),3.07 (s, 2H), 6.13 (s, 2H), 7.60 (s, 1H), 8.32 (s, 1H), 12.54 (s, 1H).419

377      0.135 (DMSO-d₆) δ 1.17 (t, J = 7.1 Hz, 3H), 1.26-1.40 (m, 1H),1.48-1.67 (m, 2H), 1.68-1.80 (m, 1H), 1.85- 1.99 (m, 1H), 1.99-2.11 (m,1H), 2.41-2.48 (m, 1H), 2.58 (s, 3H), 2.85-2.95 (m, 1H), 3.26 (s, 2H),3.54 (t, J = 4.9 Hz, 1H), 4.00-4.18 (m, 2H), 6.13 (s, 2H), 7.61 (s, 1H),8.36 (s, 1H), 12.66 (s, 1H). 420

363      0.1 (DMSO-d₆) δ 1.09 (t, J = 7.1 Hz, 3H), 1.85-2.01 (m, 3H),2.16-2.23 (m, 1H), 2.55 (s, 3H), 2.64-2.68 (m, 1H), 3.02-3.07 (m, 1H),3.50- 3.54 (m, 2H), 3.55-3.58 (m, 1H), 3.97-4.04 (m, 2H), 6.13 (s, 2H),7.60 (s, 1H), 8.31 (s, 1H), 12.59 (s, 1H). 421

319      0.187 (DMSO-d₆) δ 2.46-2.52 (m, 4H), 2.58 (s, 3H), 2.86 (t, J =6.0 Hz, 4H), 3.31 (s, 2H), 6.15 (s, 2H), 7.63 (s, 1H), 8.36 (s, 1H),12.81 (s, 1H). 422

322      0.05 2.59 (s, 3H), 2.76 (dd, J = 6.0, 3.8 Hz, 8H), 3.13 (s,2H), 6.14 (s, 2H), 7.62 (s, 1H), 8.34 (s, 1H), 12.61 (s, 1H). 423

355      1 (DMSO-d₆) δ 2.50 (s, 3H), 3.48- 3.50 (m, 2H), 3.97 (s, 2H),4.44- 4.46 (m, 2H), 6.14 (s, 2H), 6.46 (dd, J = 8.5, 1.4 Hz, 1H), 6.55-6.67 (m 1H), 6.67-6.79 (m, 2H), 7.59 (s, 1H), 8.34 (s, 1H), 12.59 (s,1H). 424

307      1.592 (DMSO-d₆) δ 1.59-1.71 (m, 1H), 2.03-2.14 (m, 1H), 2.37(dd, J = 9.6, 4.2 Hz, 1H), 2.55 (s, 3H), 2.60-2.75 (m, 2H), 3.01 (dd, J= 9.6, 6.1 Hz, 1H), 3.20-3.31 (m, 2H), 4.26-4.34 (m, 1H), 4.71 (d, J =4.9 Hz, 1H), 6.13 (s, 2H), 7.59 (s, 1H), 8.30 (s, 1H), 12.54 (s, 1H).425

323      0.643 (DMSO-d₆) δ 1.69-1.77 (m, 2H), 2.26 (s, 3H), 2.45-2.49(m, 2H), 2.56 (d, J = 1.2 Hz, 3H), 3.11 (s, 2H), 3.19 (d, J = 1.1 Hz,3H), 3.41 (td, J = 6.4, 1.2 Hz, 2H), 6.13 (d, J = 1.3 Hz, 2H), 7.60 (d,J = 1.2 Hz, 1H), 8.32 (d, J = 1.1 Hz, 1H), 12.54 (s, 1H). 426

309      1.146 (DMSO-d₆) δ 2.33 (d, J = 1.2 Hz, 3H), 2.57 (d, J = 1.2Hz, 3H), 2.67 (td, J = 6.0, 1.2 Hz, 2H), 3.18 (s, 2H), 3.21 (d, J = 1.2Hz, 3H), 3.53 (td, J = 5.9, 1.2 Hz, 2H), 6.13 (d, J = 1.2 Hz, 2H), 7.60(d, J = 1.2 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 12.55 (s, 1H). 427

337      0.373 (DMSO-d₆) δ 1.02 (t, J = 7.0 Hz, 3H), 1.63-1.73 (m, 2H),2.51-2.60 (m, 7H), 3.14 (s, 2H), 3.16 (d, J = 0.9 Hz, 3H), 3.36 (t, J =6.4 Hz, 2H), 6.13 (d, J = 0.9 Hz, 2H), 7.59 (d, J = 0.9 Hz, 1H), 8.34(d, J = 0.9 Hz, 1H), 12.57 (s, 1H). 428

478      0.650 (DMSO-d₆) δ 1.20 (br s, 3H), 1.39 (s, 9H), 2.58 (s, 3H),2.98-3.07 (m, 1H), 3.23 (br s, 1H), 3.31 (s, 1H), 3.35 (s, 1H),3.39-3.56 (m, 2H), 3.69 (s, 1H), 3.80 (br s, 1H), 4.00- 4.24 (m, 3H),6.14 (s, 2H), 7.62 (s, 1H), 8.35 (s, 1H), 12.70 (s, 1H). 429

420      1.279 (DMSO-d₆) δ 1.19-1.33 (m, 2H), 1.36 (s, 9H), 1.62-1.73(m, 3H), 2.10-2.25 (m, 2H), 2.59 (s, 3H), 2.68-2.77 (m, 1H), 3.01-3.15(m, 2H), 3.61-3.73 (m, 1H), 6.14 (s, 2H), 6.82 (d, J = 8.6 Hz, 1H), 7.62(s, 1H), 8.34 (s, 1H), 12.69 (s, 1H). 430

420      0.162 (DMSO-d₆) δ 1.38 (s, 9H), 1.57- 1.70 (m, 2H), 1.70-1.79(m, 2H), 2.14-2.24 (m, 2H), 2.57 (s, 3H), 2.72-2.81 (m, 2H), 3.09 (s,2H), 3.17-3.28 (m, 1H), 6.13 (s, 2H), 6.90 (d, J = 7.1 Hz, 1H), 7.60 (s,1H), 8.31 (s, 1H), 12.52 (s, 1H). 431

420      0.9 (DMSO-d₆) δ 1.15 (d, J = 7.0 Hz, 3H), 1.40 (s, 9H), 2.44(dt, J = 11.0, 5.3 Hz, 4H), 2.57 (s, 3H), 3.36 (q, J = 7.2 Hz, 1H),3.46-3.47 (m, 4H), 6.13 (s, 2H), 7.61 (s, 1H), 8.34 (s, 1H), 12.75 (s,1H). 432

321      1.921 (DMSO-d₆) δ 2.36-2.43 (m, 4H), 2.51-2.54 (m, 2H), 2.56(s, 3H), 2.58-2.64 (m, 2H), 3.55 (t, J = 4.7 Hz, 4H), 6.13 (s, 2H), 7.56(s, 1H), 8.07 (s, 1H), 11.77 (s, 1H). 433

349      0.22 (DMSO-d₆) δ 1.12 (d, J = 6.9 Hz, 3H), 1.59-1.67 (m, 2H),1.77 (m, 2H), 2.16-2.22 (m, 1H), 2.29-2.34 (m, 1H), 2.56 (s, 3H),2.59-2.60 (m, 1H), 2.66-2.69 (m, 1H), 3.26 (q, J = 6.9 Hz, 1H), 3.50 (m,1H), 4.25-4.27 (m, 2H), 4.32-4.35 (m, 2H), 4.59 (d, J = 3.6 Hz, 1H),7.55 (s, 1H), 8.28 (s, 1H), 12.40 (s, 1H). 434

337      0.248 (DMSO-d₆) δ 1.54-1.64 (m, 2H), 1.70-1.81 (m, 2H),2.20-2.29 (m, 2H), 2.66-2.78 (m, 2H), 3.09 (s, 2H), 3.46-3.57 (m, 1H),3.84 (s, 3H), 4.61 (d, J = 3.7 Hz, 1H), 6.12 (s, 2H), 7.40 (s, 1H), 8.29(s, 1H), 11.93 (s, 1H). 435

351      0.419 (DMSO-d₆) δ 1.55-1.68 (m, 2H), 1.82-1.91 (m, 2H),2.22-2.32 (m, 2H), 2.64-2.74 (m, 2H), 3.09 (s, 2H), 3.22 (d, J = 1.1 Hz,3H), 3.82 (d, J = 1.1 Hz, 3H), 6.10 (d, J = 1.1 Hz, 2H), 7.39 (d, J =1.1 Hz, 1H), 8.28 (d, J = 1.1 Hz, 1H), 11.95 (s, 1H). 436

323      0.287 (DMSO-d₆) δ 2.50-2.54 (m, 4H), 3.14 (s, 2H), 3.68-3.74(m, 4H), 3.85 (s, 3H), 6.12 (s, 2H), 7.41 (s, 1H), 8.29 (s, 1H), 12.02(s, 1H). 437

422    ~1 (DMSO-d₆) δ 1.40 (s, 9H), 2.47 (t, J = 5.0 Hz, 4H), 3.00-3.05(m, 4H), 3.16 (s, 2H), 3.44 (t, J = 5.0 Hz, 4H), 3.52 (t, J = 5.3 Hz,4H), 3.84 (s, 3H), 6.12 (s, 2H), 7.41 (s, 1H), 8.29 (s, 1H), 12.01 (s,1H). 438

337      0.198 (DMSO-d₆) δ 2.49-2.54 (m, 2H), 3.13 (s, 2H), 3.66-3.74(m, 4H), 3.85 (s, 3H), 4.21-4.30 (m, 2H), 4.30-4.36 (m, 2H), 7.42 (s,1H), 8.24 (s, 1H), 11.78 (s, 1H). 439

333    ~2 (DMSO-d₆) δ 1.70-1.74 (m, 4H), 2.50-2.54 (m, 4H), 2.66-2.76(m, 4H), 3.13 (s, 2H), 3.67-3.75 (m, 4H), 3.87 (s, 3H), 7.69 (s, 1H),8.39 (s, 1H), 11.72 (s, 1H). 440

293      1.821 (DMSO-d₆) δ 1.36-1.47 (m, 2H), 1.57 (p, J = 5.6 Hz, 4H),2.43-2.49 (m, 4H), 3.02 (s, 2H), 3.82 (s, 3H), 5.95 (s, 2H), 6.91 (s,1H), 7.83 (s, 1H), 9.64 (s, 1H). 441

309      1 (DMSO-d₆) δ 1.16 (d, J = 7.0 Hz, 3H), 2.46-2.54 (m, 4H), 3.27(q, J = 7.1 Hz, 1H), 3.66 (q, J = 3.9 Hz, 4H) 3.83 (s, 3H), 5.94 (s,2H), 6.91 (s, 1H), 7.78 (s, 1H), 9.74 (s, 1H). 442

311      0.2 2.63-2.78 (m, 8H), 3.08 (s, 2H), 3.81 (s, 3H), 5.93 (s,2H), 6.90 (s, 1H), 7.76 (s, 1H), 9.47 (s, 1H). 443

323      0.322 (DMSO-d₆) δ 1.07 (d, J = 6.3 Hz, 6H), 1.85-1.93 (m, 2H),2.73-2.78 (m, 2H), 3.07 (s, 2H), 3.58-3.68 (m, 2H), 3.81 (s, 3H), 5.95(s, 2H), 6.91 (s, 1H), 7.79 (s, 1H), 9.54 (s, 1H). 444

367      0.505 (DMSO-d₆) δ 1.16 (td, J = 7.1, 1.2 Hz, 3H), 2.41-2.48 (m,1H), 2.54- 2.68 (m, 2H), 2.88 (dd, J = 11.4, 3.2 Hz, 1H), 3.15 (s, 2H),3.57- 3.67 (m, 1H), 3.81 (d, J = 1.2 Hz, 3H), 3.89-3.99 (m, 1H),4.08-4.17 (m, 2H), 4.26-4.33 (m, 1H), 5.95 (d, J = 1.2 Hz, 2H), 6.90 (d,J = 1.2 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 9.40 (s, 1H). 445

367      0.526 (DMSO-d₆) δ 1.20 (td, J = 7.2, 1.2 Hz, 3H), 2.51-2.54 (m,1H), 3.00- 3.09 (m, 1H), 3.35 (d, J = 1.1 Hz, 2H), 3.56-3.68 (m, 2H),3.72-3.79 (m, 2H), 3.84 (d, J = 1.2 Hz, 3H), 4.01 (dd, J = 11.2, 3.4 Hz,1H), 4.09-4.18 (m, 2H), 5.95 (d, J = 1.2 Hz, 2H), 6.92 (d, J = 1.2 Hz,1H), 7.83 (d, J = 1.2 Hz, 1H), 9.66 (s, 1H). 446

408      0.19 (DMSO-d₆) δ 1.15 (d, J = 7.2 Hz, 3H), 1.40 (s, 9H),2.43-2.48 (m, 4H), 3.35-3.38 (m, 5H), 3.81 (s, 3H), 5.94 (s, 2H), 6.90(s, 1H), 7.77 (s, 1H), 9.68 (s, 1H). 447

293 >>10 (DMSO-d₆) δ 1.10 (t, J = 7.5 Hz, 3H), 2.46-2.48 (m, 2H),2.53-2.55 (m, 4H), 3.10 (s, 2H), 3.63-3.66 (m, 4H), 5.97 (s, 2H), 6.82(s, 1H), 7.23 (s, 1H), 9.29 (s, 1H). 448

392      0.7 (DMSO-d₆) δ 1.10 (t, J = 7.5 Hz, 3H), 1.40 (s, 9H), 2.46(m, 6H), 3.12 (s, 2H), 3.38 (t, J = 5.0 Hz, 4H), 5.97 (s, 2H), 6.82 (s,1H), 7.20 (s, 1H), 9.26 (s, 1H). 449

291      0.804 ¹H NMR (400 MHz, DMSO-d₆) δ 1.99 (p, J = 7.4 Hz, 2H),2.51-2.55 (m 4H), 2.80 (dt, J = 15.0, 7.4 Hz, 4H), 3.10 (d, J = 1.0 Hz,2H), 3.65 (t, J = 4.6 Hz, 4H), 3.84 (s, 3H), 6.94 (s, 1H), 8.05 (s, 1H),9.62 (s, 1H).Compounds with hT2R54 IC₅₀ of 104 or lower are considered especiallypotent.

EXAMPLE 18 Synthesis of1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide(154)

To a solution of1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylicacid (Example 18a) (0.2 g, 0.6 mmol) in DMF (5 mL) was addedO-(Benzotriazol-1-yl)-N,N,AP,AP-tetramethyluronium tetrafluoroborate(TBTU) (0.2 g, 0.7 mmol), TEA (0.3 mL, 1.8 mmol), and methylamine HCl(0.1 g, 0.6 mmol). The mixture was stirred at room temperature overnightand purified by reverse phase HPLC using ACN/water gradient to give thetitle compound (96 mg, 44% yield) as a white solid. MS 362 (M+H⁺).

EXAMPLE 18a1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-3-carboxylicAcid

To a solution of ethyl 1-(2-((6-acetylbenzo[d][1,3]dioxol-5-y0amino)-2-oxoethyl)piperidine-3-carboxylate (4.5 g, 12 mmol) in THF/MeOH(40/40 mL) was added LiOH (0.9 g, 42 mmol) in water (40 mL) and stirredat room temperature overnight. The solution was concentrated and usedwithout further purification. MS 349 (M+H⁺).

Compounds in Table 5 were prepared in a similar manner as in Example 18from the corresponding ester starting material described herein andcommercially available amine nucleophiles.

TABLE 5 Obs Mol hT2R54 Ion; MS IC50 SID Structure (M + H⁺) (uM) ¹H NMR(400 MHz) 154

362 0.024 (DMSO-d₆) δ 1.31 (qd, J = 13.0, 4.5 Hz, 1H), 1.57-1.66 (m,1H), 1.69-1.84 (m, 2H), 2.01-2.10 (m, 1H), 2.21 (t, J = 11.0 Hz, 1H),2.53 (d, J = 4.6 Hz, 3H), 2.57 (s, 3H), 2.75 (br d, J = 10.8 Hz, 1H),2.83 (br dd, J = 11.2, 4.0 Hz, 1H), 3.06 (d, J = 16.8 Hz, 1H), 3.15 (d,J = 16.8 Hz, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 7.77 (d, J = 4.8 Hz, 1H),8.34 (s, 1H), 12.57 (s, 1H). 155

376 0.210 (DMSO-d₆) δ 0.97 (t, J = 7.2 Hz, 3H), 1.24-1.39 (m, 1H),1.54-1.65 (m, 1H), 1.70- 1.86 (m, 2H), 1.99-2.11 (m, 1H), 2.22 (t, J =11.0 Hz, 1H), 2.52-2.60 (m, 4H), 2.75 (br d, J = 10.8 Hz, 1H), 2.83 (brdd, J = 13.6, 3.6 Hz, 1H), 2.97-3.08 (m, 3H), 3.17 (d, J = 16.7 Hz, 1H),6.13 (s, 2H), 7.61 (s, 1H), 7.83 (t, J = 5.5 Hz, 1H), 8.33 (s, 1H),12.56 (s, 1H). 156

438 0.114 (DMSO-d₆) δ 1.36 (qd, J = 12.5, 3.9 Hz, 1H), 1.56- 1.70 (m,1H), 1.70-1.97 (m, 2H), 2.02-2.13 (m, 1H), 2.27 (t, J = 11.0 Hz, 1H),2.56 (s, 3H), 2.68 (tt, J = 11.5, 3.7 Hz, 1H), 2.77 (br d, J = 11.2 Hz,1H), 2.89 (br dd, J = 11.6, 3.6 Hz, 1H), 3.06 (d, J = 16.8 Hz, 1H), 3.19(d, J = 16.8 Hz, 1H), 4.24 (d, J = 6.0 Hz, 2H), 6.13 (s, 2H), 7.16-7.26(m, 3H), 7.25- 7.35 (m, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 8.41 (t, J =6.0 Hz, 1H), 12.57 (s, 1H). 157

424 0.565 (DMSO-d₆) δ 1.41 (qd, J = 12.5, 3.9 Hz, 1H), 1.62- 1.70 (m,1H), 1.79-2.01 (m, 2H), 2.08 (dd, J = 11.9, 9.2 Hz, 1H), 2.35 (t, J =11.0 Hz, 1H), 2.59 (s, 3H), 2.76-2.87 (m, 2H), 2.96 (br d, J = 11.0 Hz,1H), 3.05 (d, J = 16.8 Hz, 1H), 3.26 (d, J = 16.8 Hz, 1H), 6.14 (d, J =1.0 Hz, 2H), 6.95-7.08 (m, 1H), 7.23-7.29 (m, 2H), 7.55- 7.65 (m, 3H),8.34 (s, 1H), 9.99 (s, 1H), 12.58 (s, 1H). 158

376 0.107 (DMSO-d₆) δ 1.25-1.40 (m, 1H), 1.61-1.70 (m, 1H), 1.71-1.85(m, 2H), 2.15 (t, J = 11.1 Hz, 2H), 2.57 (s, 3H), 2.72-2.86 (m, 5H),2.98 (s, 3H), 3.04 (d, J = 16.8 Hz, 1H), 3.09-3.19 (m, 1H), 3.20 (d, J =16.8 Hz, 1H), 6.14 (s, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.61 (s, 1H).159

418 0.497 (DMSO-d₆) δ 1.27-1.46 (m, 1H), 1.61-1.84 (m, 3H), 2.11-2.25(m, 2H), 2.58 (s, 3H), 2.72-2.79 (m, 1H), 2.84 (d, 11.1 Hz, 1H), 3.05(d, J = 16.8 Hz, 1H), 3.07- 3.16 (m, 1H), 3.21 (d, J = 16.8 Hz,3.36-3.56 (m, 8H), 6.14 (br s, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.58(s, 1H). 160

362 1.27 (DMSO-d₆, rotamers) δ 1.31-1.45 (m, 2H), 1.48- 1.85 (m, 5H),2.24-2.39 (m, 1H), 2.55-2.74 (m, 5H), 2.79-2.90 (m, 1H), 2.92-3.09 (m,2H), 3.10- 3.25 (m, 2H), 6.13-6.16 (m, 2H), 7.57-6.66 (three s, 1H),7.71-7.80 (m, 1H), 8.13-8.65 (three s, 1H), 12.20-12.60 (three s, 1H).161

362 1.35 (DMSO-d₆) δ 1.66 (br d, J = 12.7 Hz, 2H), 1.83 (qd, J = 12.0,3.7 Hz, 2H), 2.01-2.16 (m, 3H), 2.56 (s, 1.5H), 2.57 (s, 4.5H), 2.84 (brd, J = 11.4 Hz, 2H), 3.08 (s, 2H), 6.13 (s, 2H), 7.61 (s, 1H), 7.69 (m,1H), 8.32 (s, 1H), 12.52 (s, 1H). 162

376 0.747 (DMSO-d₆) δ 1.00 (t, J = 7.2 Hz, 3H), 1.65 (br d, J = 12.7 Hz,2H), 1.83 (qd, J = 12.1, 3.6 Hz, 2H), 1.99-2.17 (m, 3H), 2.57 (s, 3H),2.84 (dt, J = 11.2, 3.6 Hz, 2H), 3.00- 3.12 (m, 4H), 6.13 (s, 2H), 7.61(s, 1H), 7.74 (t, J = 5.6 Hz, 1H), 8.32 (s, 1H), 12.51 (s, 1H). 163

425 0.459 (DMSO-d₆) δ 1.76-2.03 (m, 3H), 2.14-2.26 (m, 2H), 2.30-2.42(m, 2H), 2.44- 2.57 (m, 2H), 2.58 (2, 3H), 2.65-2.68 (m, 05H), 2.87-2.95 (m, 2.5H), 3.13 (s, 2H), 6.14 (s, 2H), 7.29-7.37 (m, 1H), 7.62 (s,1H), 8.04-8.08 (m, 1H), 8.24 (dd, J = 4.7, 1.5 Hz, 1H), 8.33 (s, 1H),8.73-8.78 (m, 1H), 10.11 (s, 1H), 12.56 (s, 1H). 164

424 2.09 (DMSO-d₆) δ 1.78 (br d, J = 12.7 Hz, 2H), 1.94 (qd, J = 12.2,3.6 Hz, 2H), 2.14- 2.23 (m, 2H), 2.29-2.39 (m, 1H), 2.58 (s, 3H), 2.91(br d, J = 11.4 Hz, 2H), 3.12 (s, 2H), 6.14 (s, 2H), 6.96- 7.09 (m, 1H),7.22-7.37 (m, 2H), 7.55-7.68 (m, 3H), 8.33 (s, 1H), 9.88 (s, 1H), 12.55(s, 1H). 165

438 1.40 (DMSO-d₆) δ 1.71 (br d, J = 12.6 Hz, 2H), 1.88 (qd, J = 12.1,11.6, 3.7 Hz, 2H), 2.07-2.26 (m, 3H), 2.57 (m, 3H), 2.86 (dt, J = 11.3,3.2 Hz, 2H), 3.10 (s, 2H), 4.27 (d, J = 5.9 Hz, 2H), 6.13 (s, 2H),7.18-7.26 (m, 3H), 7.28-7.35 (m, 2H), 7.61 (s, 1H), 8.23-8.38 (m, 2H),12.54 (s, 1H). 450

364 0.668 (DMSO-d₆) δ 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.43 (m, 1H),1.43-1.58 (m, 1H), 1.64- 1.79 (m, 2H), 2.07-2.17 (m, 1H), 2.25-2.35 (m,1H), 2.34-2.42 (m, 1H), 2.73 (d, J = 11.3 Hz, 1H), 2.82 (d, J = 10.6 Hz,1H), 2.97-3.08 (m, 3H), 3.13 (d, J = 16.5 Hz, 1H), 3.82 (s, 3H), 5.95(s, 2H), 6.91 (s, 1H), 7.79 (s, 1H), 7.85 (t, J = 5.5 Hz, 1H), 9.53 (s,1H). 451

400 0.406 (DMSO-d₆) δ 2.29 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 2.73 (t, J= 7.1 Hz, 2H), 3.11 (s, 2H), 3.76 (s, 3H), 4.25 (d, J = 5.8 Hz, 2H),5.95 (s, 2H), 6.89 (s, 1H), 7.22 (d, J = 7.4 Hz, 3H), 7.25-7.32 (m, 2H),7.76 (s, 1H), 8.41 (t, J = 5.8 Hz, 1H), 9.35 (s, 1H). 452

426 0.603 (DMSO-d₆) δ 1.34-1.63 (m, 3H), 1.67-1.76 (m, 1H), 1.78-1.86(m, 1H), 2.10- 2.19 (m, 1H), 2.36 (t, J = 10.8 Hz, 1H), 2.70-2.78 (m,1H), 2.84-2.92 (m, 1H), 3.03 (d, J = 16.6 Hz, 1H), 3.15 (d, J = 16.5 Hz,1H), 3.81 (s, 3H), 4.20-4.30 (m, 2H), 5.95 (s, 2H), 6.90 (s, 1H),7.16-7.25 (m, 3H), 7.27-7.32 (m, 2H), 7.79 (s, 1H), 8.42 (t, J = 6.0 Hz,1H), 9.55 (s, 1H). 453

350 0.969 (DMSO-d₆) δ 1.30-1.43 (m, 1H), 1.44-1.59 (m, 1H), 1.64-1.80(m, 2H), 2.06- 2.18 (m, 1H), 2.23-2.44 (m, 2H), 2.54 (d, J = 4.5 Hz,3H), 2.73 (d, J = 11.5 Hz, 1H), 2.82 (d, J = 10.7 Hz, 1H), 3.02 (d, J =16.3 Hz, 1H), 3.12 (d, J = 16.5 Hz, 1H), 3.82 (s, 3H), 5.95 (s, 2H),6.91 (s, 1H), 7.77- 7.83 (m, 2H), 9.53 (s, 1H).Compounds with hT2R54 IC₅₀ of 104 or lower are considered especiallypotent.

EXAMPLE 19 Synthesis of2-(4-Acetamidopiperidin-1-yl)-N-(6-acetylbenzo[d][1,3]dioxol-5-yl)acetamide(166)

To a solution ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamidedihydrochloride (Example 19a) (0.2 g, 0.5 mmol) in DCM (5 mL) was addedacetyl chloride (0.04 g, 5 mmol) and TEA (0.3 mL, 2 mmol). The mixturewas stirred overnight at room temperature and purified by reverse phaseHPLC using ACN/water gradient to give the desired product (91 mg, 50%yield) as a white solid. MS 362 (M+H⁺).

EXAMPLE 19aN-(6-Acelylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamidedihydrochloride

To a solution of tert-butyl(1-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidin-4-yl)carbamate(Example 19b) (3.3 g, 8 mmol) in anhydrous DCM (10 mL) was added 4M HClin dioxane (10 mL). The reaction was allowed stir at room temperatureovernight. The reaction was filtered, the solid washed successively withDCM and ether, and dried under vacuum to give the title compound (3.1 g,quantitative yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6) δ1.85-2.21 (m, 5H), 2.58 (s, 3H), 3.19 (s, 3H), 4.25 (s, 2H), 6.17 (s,2H), 7.61 (s, 1H), 7.81 (s, 1H), 8.45 (s, 3H), 10.43 (s, 1H), 11.77 (s,1H).

EXAMPLE 19b tert-Butyl(1-(24(6-Acetylbenzol[1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidin-4-yl)carbamate

Prepared in a similar manner as in Example 9 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-chloroacetamide (Example 14a)(2.5 g, 10 mmol) and tert-butyl piperidin-4-ylcarbamate (2 g, 10 mmol)to give the desired product (3.3 g, 79% yield) as a light brown solid.

Compounds in Table 6 were prepared in a similar manner as in Example 2,Example 18, and/or Example 19 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(4-aminopiperidin-1-yl)acetamidedihydrochloride (Example 19a) and the corresponding commerciallyavailable carboxylic acids and/or acyl chlorides.

TABLE 6 Obs Mol hT2R54 ion MS; IC50 SID Structure (M + H⁺) (uM) ¹H NMR(400 MHz) 166

362 0.264 (DMSO-d₆) δ 1.56-1.79 (m, 4H), 1.80 (s, 3H), 2.15-2.29 (m,2H), 2.57 (s, 3H), 2.78 (d, J = 11.7 Hz, 2H), 3.10 (s, 2H), 3.53 (td, J= 11.3, 6.6 Hz, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 7.89 (d, J = 7.4 Hz,1H), 8.33 (s, 1H), 12.55 (s, 1H). 167

376 0.31 (DMSO-d₆) δ 0.98 (t, J = 7.6 Hz, 3H), 1.56-1.80 (m, 4H), 2.07(q, J = 7.6 Hz, 2H), 2.17- 2.26 (m, 2H), 2.57 (s, 3H), 2.75-2.82 (m,2H), 3.10 (s, 2H), 3.44-3.60 (m, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 7.80(d, J = 7.2 Hz, 1H), 8.33 (s, 1H), 12.54 (s, 1H). 168

390 0.14 (DMSO-d₆) δ 0.98 (d, J = 6.8 Hz, 6H), 1.58-1.80 (m, 4H),2.14-2.27 (m, 2H), 2.33-2.43 (m, 1H), 2.58 (s, 3H), 2.79 (br dt, J =11.1, 4.0 Hz, 2H), 3.10 (s, 2H), 3.45-3.59 (m, 1H), 6.13 (s, 2H), 7.61(s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 8.32 (s, 1H), 12.54 (s, 1H). 169

404 0.14 (DMSO-d₆) δ 0.82-0.90 (m, 6H), 1.56-1.81 (m, 4H), 1.91- 2.01(m, 3H), 2.17-2.26 (m, 2H), 2.57 (s, 3H), 2.79 (br d, J = 11.4 Hz, 2H),3.10 (s, 2H), 3.50-3.61 (m, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 7.82 (d, J= 7.5 Hz, 1H), 8.32 (s, 1H), 12.54 (s, 1H). 170

418 0.188 (DMSO-d₆) δ 0.83-0.94 (d, J = 5.6 Hz, 6H), 1.11-1.44 (m, 3H),1.55-1.66 ( (m, 2H), 1.90-2.02 (m, 2H), 2.04-2.15 (m, 2H), 2.36- 2.54(m, 1H), 2.57 (s, 3H), 2.81 (br d, J = 10.5 Hz, 2H), 2.96 (br t, J = 5.4Hz, 2H), 3.08 (s, 2H), 6.13 (s, 2H), 7.61 (s, 1H), 7.81 (t, J = 5.6 Hz,1H), 8.33 (s, 1H), 12.56 (s, 1H). 171

424 0.06 (DMSO-d₆) δ 1.77-1.96 (m, 4H), 2.26 (td, J = 11.2, 10.8, 4.2Hz, 2H), 2.58 (s, 3H), 2.87 (br d, J = 11.6 Hz, 2H), 3.14 (s, 2H), 3.74-3.84 (m, 1H), 6.14 (s, 2H), 7.40-7.48 (m, 2H), 7.48- 7.55 (m, 1H), 7.62(s, 1H), 7.84-7.91 (m, 2H), 8.33 (s, 1H), 8.42 (d, J = 7.4 Hz, 1H),12.54 (s, 1H). 172

414 0.69 (DMSO-d₆) δ 1.74-1.91 (m, 4H), 2.24 (td, J = 11.5, 3.0 Hz, 2H),2.58 (s, 3H), 2.85 (br d, J = 11.6 Hz, 2H), 3.13 (s, 2H), 3.66-3.81 (m,1H), 6.14 (s, 2H), 6.60 (dd, J = 3.4, 1.7 Hz, 1H), 7.16 (dd, J = 3.5,0.8 Hz, 1H), 7.62 (s, 1H), 7.81 (dd, J = 1.8, 0.8 Hz, 1H), 8.30 (d, J =8.0 Hz, 1H), 8.32 (s, 1H), 12.52 (s, 1H). 173

430 0.11 (DMSO-d₆) δ 1.78-1.90 (m, 4H), 2.24 (td, J = 11.1, 4.9 Hz, 2H),2.59 (s, 3H), 2.87 (br d, J = 11.3 Hz, 2H), 3.13 (s, 2H), 3.68-3.81 (m,1H), 6.14 (s, 2H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H), 7.62 (s, 1H), 7.73(dd, J = 5.0, 1.1 Hz, 1H), 7.88 (dd, J = 3.8, 1.1 Hz, 1H), 8.33 (s, 1H),8.43 (d, J = 7.4 Hz, 1H), 12.54 (s, 1H). 174

425 0.27 (DMSO-d₆) δ 1.83-1.94 (m, 4H), 2.27-2.38 (m, 2H), 2.59 (s, 3H),2.84 (br d, J = 11.5 Hz, 2H), 3.15 (s, 2H), 3.77-3.88 (m, 1H), 6.14 (s,2H), 7.57-7.66 (m, 2H), 7.96-8.07 (m, 2H), 8.33 (s, 1H), 8.48 (d, J =7.9 Hz, 1H), 8.66 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 12.56 (s, 1H). 175

425 0.11 (DMSO-d₆) δ 1.81-1.91 (m, 4H), 2.21-2.34 (m, 2H), 2.58 (s, 3H),2.88 (br d, J = 11.5 Hz, 2H), 3.14 (s, 2H), 3.76-3.86 (m, 1H), 6.14 (s,2H), 7.49 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.62 (s, 1H), 8.21 (dt, J =8.0, 2.0 Hz, 1H), 8.33 (s, 1H), 8.63 (d, J = 7.3 Hz, 1H), 8.69 (dd, J =4.8, 1.6 Hz, 1H), 9.02 (dd, J = 2.3, 0.8 Hz, 1H), 12.55 (s, 1H). 176

425 0.45 (DMSO-d₆) δ 1.78-1.91 (m, 4H), 2.26 (td, J = 11.3, 10.9, 4.6Hz, 3H), 2.58 (s, 3H), 2.88 (br d, J = 11.6 Hz, 2H), 3.14 (s, 2H),3.71-3.87 (m, 1H), 6.14 (s, 2H), 7.62 (s, 1H), 7.73-7.82 (m, 2H), 8.33(s, 1H), 8.66-8.75 (m, 3H), 12.54 (s, 1H). 177

404 0.20 (DMSO-d₆) δ 0.88 (d, J = 6.6 Hz, 6H), 1.09-1.32 (m, 2H),1.79-2.03 (m, 3H), 2.09-2.22 (m, 2H), 2.54 (s, 3H), 2.57-2.75 (m, 3H),2.95-3.08 (m, 1H), 3.26- 3.31 (m, 2H), 3.83 (br d, J = 13.7 Hz, 1H),4.22 (br d, J = 13.2 Hz, 1H), 6.13 (s, 2H), 7.59 (s, 1H), 8.36 (s, 1H),12.66 (s, 1H). 178

414 0.06 (DMSO-d₆) δ 1.18 (t, J = 7.3 Hz, 1H), 1.22-1.43 (m, 2H), 1.95(br d, J = 12.8 Hz, 2H), 2.55 (s, 3H), 2.63-2.80 (m, 2H), 2.97- 3.29 (m,4H), 3.29-3.40 (m, 1H), 4.20 (br d, J = 13.2 Hz, 2H), 6.13 (s, 2H), 6.61(dd, J = 3.4, 1.8 Hz, 1H), 6.94 (dd, J = 3.5, 0.8 Hz, 1H), 7.59 (s, 1H),7.82 (dd, J = 1.8, 0.8 Hz, 1H), 8.34 (s, 1H), 12.63 (s, 1H). 179

425 0.09 (DMSO-d₆) δ 1.20-1.43 (m, 3H), 1.77-2.04 (m, 2H), 2.56 (s, 3H),2.64- 2.74 (m, 2H), 2.88-3.21 (m, 3H), 3.32 (s, 2H), 3.48-3.60 (m, 1H),4.22- 4.38 (m, 1H), 6.13 (s, 2H), 7.47 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H),7.59 (s, 1H), 7.79 (dt, J = 7.8, 1.9 Hz, 1H), 8.35 (s, 1H), 8.57 (dd, J= 2.3, 0.9 Hz, 1H), 8.64 (dd, J = 4.9, 1.7 Hz, 1H), 12.65 (s, 1H). 180

418 0.589 (DMSO-d₆) δ 0.90 (d, J = 6.6 Hz, 6H), 1.36-1.45 (br d, 1.2H),1.49-1.57 (br d, 0.8H), 1.89-2.45 (m, 8H), 2.58 (s, 3H), 2.74-2.94 (m,6H), 3.13 (two s, 2H), 3.60-3.75 (m, 0.35H), 4.30-4.43 (m, 0.65H), 6.13(s, 2H), 7.61 (s, 1H), 8.35 (s, 1H), 12.66-12.72 (two s, 1H). 181

428 0.676 (DMSO-d₆) δ 1.56-1.68 (m, 2H), 2.07-2.22 (m, 2H), 2.32 (br t,J = 12.2 Hz, 2H), 2.59 (s, 3H), 2.89 (br d, J = 10.8 Hz, 2H), 3.06 (brs, 2H), 3.14 (s, 3H), 3.84-4.55 (m, 2H), 6.14 (s, 2H), 6.62 dd, J = 3.2,1.6 Hz, 1H), 6.99 (br-s, 1H), 7.62 (s, 1H), 7.84 (dd, J = 1.6, 0.8 Hz,1H), 8.35 (s, 1H), 12.72 (s, 1H). 182

439 0.455 (DMSO-d₆) δ 1.63 (br s, 2H), 2.95-2.25 (m, 4H), 2.25-2.40 (m,2H), 2.52- 2.63 (m, 4H), 2.71-3.20 (m, 5H), 4.40 (br s, 1H), 6.13 (s,2H), 7.44-7.53 (m, 1H), 7.61 (s, 1H), 7.84 (br s, 1H), 8.34 (br s, 1H),8.55-8.71 (m, 2H), 12.69 (s, 1H).Compounds with hT2R54 IC₅₀ of 104 or lower are considered especiallypotent.

EXAMPLE 20 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-((1-(furan-2-carbonyl)piperidin-4-yl)(methyl)amino)acetamide(183)

Prepared in a similar manner as in Example 19 fromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamidedihydrochloride (Example 20a) (0.2 g, 0.5 mmol), furan-2-carbonylchloride (0.08 g, 0.6 mmol), and TEA (0.3 mL, 2 mmol) to give the titlecompound(119 mg, 56% yield) as a white solid. MS 428 (M+H⁺).

EXAMPLE 20aN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamideDihydrochloride

Prepared in a similar manner as in Example 19a from tert-butyl4-((2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate(Example 20b) to give ˜1.1 g (quantitative yield) of the desiredproduct.

EXAMPLE 20b tert-Butyl4-((2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)(methyl)amino)piperidine-1-carboxylate

Prepared in a similar manner as in Example 9 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-chloroacetamide (Example 14a)(1.2 g, 4.7 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (1g, 4.7 mmol), and TEA to give ˜1.2 g (60% yield) of the title compoundas white solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.27-1.44 (m, 2H), 1.39 (s,9H), 1.80 (d, J=12.4 Hz, 2H), 2.27 (s, 3H), 2.55 (s, 3H), 2.57-2.76 (m,3H), 3.17 (s, 2H), 3.98 (d, J=13.2 Hz, 2H), 6.13 (s, 2H), 7.60 (s, 1H),8.33 (s, 1H), 12.68 (s, 1H). MS 434 (M+H⁺).

EXAMPLE 21 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(1-(3-methylbutanoyl)piperidin-4-yl)amino)acetamide(184)

Prepared in a similar manner as in Example 19 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamidedihydrochloride (Example 20a) (0.2 g, 0.5 mmol) and 3-methylbutanoylchloride (0.07 g, 0.6 mmol) to give the desired product (118 mg, 56%yield) as a white solid. MS 418 (M+H⁺).

Compounds in Table 7 were prepared in a similar manner as in Example 19fromfromN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(methyl(piperidin-4-yl)amino)acetamidedihydrochloride (Example 20a) and the corresponding commerciallyavailable carboxylic acids and/or acyl chlorides.

TABLE 7 Obs Mol hT2R54 Ion MS; IC50 SID Structure (M + H⁺) (uM) ¹H NMR(400 MHz) 183

428 0.061 (DMSO-d₆) δ 1.46 (d, J = 12.8 Hz, 2H), 1.91 (d, J = 12.3 Hz,2H), 2.29 (s, 3H), 2.55 (s, 3H), 2.75-2.81 (m, 3H), 3.20 (s, 2H), 4.37(bs, 2H), 6.13 (s, 2H), 6.61 (dd, J = 3.5, 1.8 Hz, 1H), 6.96 (dd, J =3.4, 0.8 Hz, 1H), 7.60 (s, 1H), 7.82 (dd, J = 1.8, 0.8 Hz, 1H), 8.34 (s,1H), 12.69 (s, 1H). 184

418 0.098 (DMSO-d₆) δ 0.88 (m, J = 6.6, 1.4 Hz, 6H), 1.21-1.43 (m, 2H),1.84 (br t, J = 15.4 Hz, 2H), 1.90-2.02 (m, 1H), 2.17 (dd, J = 7.0, 1.9Hz, 2H), 2.28 (s, 3H), 2.55 (s, 3H), 2.61-2.73 (m, 1H), 2.97 (br t, J =12.3 Hz, 1H), 3.17 (s, 2H), 3.93 (br d, J = 13.6 Hz, 1H), 4.45 (br d, J= 13.0 Hz, 1H), 6.13 (s, 2H), 7.60 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H).185

418 0.05 (DMSO-d₆, rotamers) δ 0.81-0.89 (m, 6H), 1.13- 1.40 (m, 1H),1.41-1.58 (m, 1H), 1.65-1.83 (m, 1H), 1.89-2.01 (m, 2H), 2.15 (d, J =6.9 Hz, 2H), 2.27-2.44 (m, 4H), 2.43- 2.72 (m, 4H), 2.87-3.04 (m, 1H),3.14-3.42 (m, 2H), 3.73 (br d, J = 13.5 Hz, 0.5H), 4.11 (br d, J = 13.0Hz, 0.5H), 4.35 (br d, J = 12.9 Hz, 0.5H), 4.44 (br d, J = 12.1 Hz,0.5H), 6.13 (s, 1H), 6.14 (s, 1H), 7.60 (s, 0.5H), 7.62 (s, 0.5H), 8.33(s, 0.5H), 8.35 (s, 0.5H), 12.64 (s, 0.5H), 12.75 (s, 0.5H). 186

428 0.02 (DMSO-d₆) δ 1.36-1.49 (m, 1H), 1.52-1.67 (m, 1H), 1.77-1.86 (m,1H), 1.95-2.05 (m, 1H), 2.35 (s, 3H), 2.51-2.70 (m, 4H), 2.98 (br s,2H), 3.18-3.29 (m, 2H), 4.21 (br-s, 1H), 4.43 (br d, J = 12.5 Hz, 1H),6.13 (s, 2H), 6.58 (dd, J = 3.4, 1.8 Hz, 1H), 6.91 (dd, J = 3.5, 0.8 Hz,1H), 7.60 (s, 1H), 7.77 (br s, 1H), 8.33 (s, 1H), 12.70 (s, 1H). 187

439 0.10 (DMSO-d₆, roramers) δ 1.37-1.85 (m, 3H), 1.97 (br d, J = 11.8Hz, 1H), 2.16-2.79 (m, 8H), 2.86-3.48 (m, 4H), 3.74 (br d, J = 13.1 Hz,0.5H), 4.37-4.58 (m, 1H), 6.12 (s, 2H), 7.34 (br s, 0.5H), 7.46 (br s,0.5), 7.53-7.66 (m, 1H), 7.77 (d, J = 7.8 Hz, 1H), 8.27-7.39 (m, 1H),8.53-8.69 (m, 2H), 12.61 (s, 0.5H), 12.70 (s, 0.5H). 188

406 0.09 (DMSO-d₆) δ 1.12 (t, J = 7.1 Hz, 3H), 1.24- 1.53 (m, 2H),1.67-1.77 (m, 1H), 1.86-1.94 (m, 1H), 2.32 (s, 3H), 2.56 (s, 3H),2.62-2.90 (m, 3H), 3.19 (d, J = 16.8 Hz, 1H), 3.27 (d, J = 16.8 Hz, 1H),3.79 (br d, J = 12.9 Hz, 1H), 3.94 (br q, J = 7.1 Hz, 2H), 4.06 (br d, J= 12.6 Hz, 1H), 6.11 (s, 2H), 7.59 (s, 1H), 8.32 (s, 1H), 12.65 (s, 1H).189

405 0.03 (DMSO-d₆) δ 0.98 (t, J = 7.1 Hz, 3H), 1.23-1.46 (m, 2H),1.61-1.71 (m, 1H), 1.96 (br d, J = 11.8 Hz, 1H), 2.33 (s, 3H), 2.35-2.45(m, 1H), 2.46- 2.59 (m, 5H), 2.96-3.06 (m, 2H), 3.18 (d, J = 17.2 Hz,1H), 3.30 (d, J = 17.2 Hz, 1H), 3.82 (br d, J = 13.3 Hz, 1H), 4.10 (brd, J = 12.4 Hz, 1H), 6.13 (s, 2H), 6.39 (t, J = 5.4 Hz, 1H), 7.60 (s,1H), 8.33 (s, 1H), 12.64 (s, 1H). 190

440 0.04 (DMSO-d₆) δ 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.52 (m, 2H),1.62-1.74 (m, 2H), 1.75-1.83 (m, 1H), 1.95 (br d, J = 11.5 Hz, 1H), 2.34(s, 3H), 2.56 (s, 3H), 2.59-2.69 (m, 2H), 2.74 (t, J = 11.0 Hz, 1H),2.92-3.06 (m, 2H), 3.18-3.35 (m, 2H), 3.50 (br d, J = 11.9 Hz, 1H), 3.74(br d, J = 11.0 Hz, 1H), 6.13 (s, 2H), 7.61 (s, 1H), 8.33 (s, 1H), 12.65(s, 1H).Compounds with hT2R54 IC₅₀ of 104 or lower are considered especiallypotent.

EXAMPLE 22 Synthesis of Ethyl1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-4-(furan-2-carbonyl)piperazine-2-carboxylate(191, IC₅₀=16 nM)

Prepared in a similar manner as in Example 19 from ethyl1-(2-((6-acetylbenzo-[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-2-carboxylatedihydrochloride (Example 22a) (0.45 g, 1 mmol), furan-2-carbonylchloride (0.13 g, 1 mmol), and TEA (0.6 mL, 4 mmol) to give the desiredproduct (94 mg, 20% yield) as an off white solid. ¹H NMR (400 MHz,DMSO-d6) δ 1.05 (brs, 3H), 2.60 (s, 3H), 2.65 (d, J=12.2 Hz, 1H),3.00-3.16 (m, 1H), 3.35-3.54 (m, 2H), 3.82 (t, J=3.1 Hz, 2H), 3.99 (d,J=7.6 Hz, 2H), 4.22 (d, J=13.0 Hz, 1H), 4.64 (brs, 1H), 6.15 (s, 2H),6.63 (dd, J=3.5, 1.8 Hz, 1H), 7.04 (d, J=3.4 Hz, 1H), 7.64 (s, 1H), 7.85(dd, J=1.8, 0.8 Hz, 1H), 8.37 (s, 1H), 12.77 (s, 1H). MS 472 (M+H⁺).

EXAMPLE 22a Ethyl1-(24(6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-piperazine-2-carboxylateDihydrochloride

Prepared in a similar manner as in Example 19a from 1-(tert-butyl)3-ethyl4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1,3-dicarboxylate(Example 22b) (1.4 g, 3 mmol) to give desired product (1.35 g,quantitative yield).

EXAMPLE 22b 1-(tert-Butyl)3-ethyl4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-1,3-dicarboxylate

Prepared in a similar manner as in Example 9 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-chloroacetamide (Example 14a) (1g, 4 mmol), 1-(tert-butyl) 3-ethyl piperazine-1,3-dicarboxylate (1.0 g,4 mmol) and TEA (1.7 mL, 12 mmol) to give ˜1.4 g (75% yield) of thedesired material as white solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.20 (br s,3H), 1.39 (s, 9H), 2.58 (s, 3H), 3.00-3.06 (m, 1H), 3.39-3.59 (m, 2H),3.64-3.87 (m, 2H), 4.04-4.26 (m, 3H), 6.14 (s, 2H), 7.62 (s, 1H), 8.35(s, 1H), 12.70 (s, 1H). MS 478 (M+H⁺).

EXAMPLE 23 Synthesis of Ethyl1-(2-((6-Acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)-4-(3-methylbutanoyl)piperazine-2-carboxylate(192, IC₅₀=57 nM)

Prepared in a similar manner as in Example 20 from ethyl1-(2-((6-acetylbenzo-[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperazine-2-carboxylatedihydrochloride (Example 22a) (0.45 g, 1 mmol) and 3-methylbutanoylchloride (0.12 g, 1 mmol) to give the desired product (82 mg, 18% yield)as a white solid. MS 462 (M+H⁺).

EXAMPLE 24 Synthesis ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(3-methylbutanoyl)piperidin-3-yl)acetamide(193)

A solution ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide HClsalt (53 mg, 0.156 mmol) and TEA (44 μL, 0.336 mmol) in dry DCM (4 mL)was treated with isovaleryl chloride (21 uL, 0.172 mmol) and thesolution was stirred overnight at room temperature. The solvent wasremoved under vacuum and the residue purified by silica gelchromatography to afford the title compound as a colorless oil (64.4 mg,quantitative yield). MS 389 (M+H⁺).

EXAMPLE 24aN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide

A solution of tert-butyl3-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-1-carboxylate(Example 24b) (5.9 g) in 4M HCl in 1,4-dioxane (80 mL) was stirredovernight at room temperature. The precipitate was collected byfiltration to give the title compound as a pale yellow solid inquantitative yield.

EXAMPLE 24b tert-Butyl3-(2-((6-Acetylbenzo[1,3]dioxol-5-yl)amino)-2-oxoethyl)-piperidine-1-carboxylate

A mixture of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one (3.07 g,17.13 mmol), 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid (5.0g, 20.6 mmol), HATU (9.78 g, 25.70 mmol), and DIEA (8.95 mL, 51.40 mmol)in dry DMF was heated to 55° C., and stirred overnight at roomtemperature. The reaction mixture was concentrated and the residue wasdiluted with EtOAc and washed successively with water and brine.

The organic phase was dried over MgSO₄, filtered, and concentrated onthe rotavap. The residue was purified by silica gel chromatography using20%-30% EtOAc in Hexanes as eluent. The fractions were collected anddried to give the title compound as a yellowish oil (5.9 g, 14.6 mmol,85% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.23 (m, 2H), 1.35 (s, 9H),1.56-1.62 (m, 1H), 1.73-1.79 (m, 1H), 1.88 (br. s, 1H), 2.28 (m, 2H),2.57 (s, 3H), 2.84 (br. s, 2H), 3.71-3.83 (m, 2H), 6.14 (s, 2H), 7.59(s, 1H), 8.12 (s, 1H), 11.83 (s, 1H).

EXAMPLE 25 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-2-carbonyl)piperidin-3-yl)acetamide(194)

Prepared in a similar manner as in Example 24 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-3-yl)acetamide HClsalt (Example 24a) (42 mg, 0.123 mmol), and 2-furoyl chloride (13 uL,0.135 mmol) to afford the title compound as a white solid (44.1 mg, 90%yield). MS 399 (M+H+).

EXAMPLE 26 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(thiophene-2-carbonyl)piperidin-3-yl)acetamide(195)

Prepared in a similar manner as in Example 24 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-3-yl)acetamide HClsalt (Example 24a) (41 mg, 0.120 mmol) and thiophene-2-carbonyl chloride(14 uL, 0.132 mmol) to afford the title compound as a white solid (47.6mg, 96% yield). MS 415 (M+H⁺).

EXAMPLE 27 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-3-carbonyl)piperidin-3-yl)acetamide(196)

A solution of 3-furoic acid (18 mg, 0.161 mmol) and DIEA (51 μL, 0.294mmol) in dry DCM (4 mL) was treated with TBTU (61 mg, 0.191 mmol) andthe solution was stirred for 1 hour at room temperature.N-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide HClsalt (Example 24a) (50 mg, 0.147 mmol) was then added and the mixturestirred overnight at room temperature. The solvent was removed undervacuum and the residue purified by silica gel chromatography using 0-50%EtOAc in hexanes as eluent to afford the title compound as a whitepowder (66.5 mg, quantitative yield). MS 399 (M+H⁺).

EXAMPLE 28 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-2-carbonyl)piperidin-4-yl)acetamide(197)

Prepared in a similar manner as in Example 24 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide HClsalt (Example 28a) (42 mg, 0.123 mmol), TEA (34 uL, 0.246 mmol), and2-furoyl chloride (13 uL, 0.135 mmol) to afford the title compound as awhite solid (44 mg, 90% yield). MS 399 (M+H⁺).

EXAMPLE 28aN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-4-yl)acetamidehydrochloride

Prepared in a similar manner as in Example 24a from tert-butyl4-(2-((6-acetylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-1-carboxylate(Example 28b) (699 mg, 1.73 mmol) and 4N HCl in dioxane (4.5 mL) toafford the title compound as a yellow solid (556 mg, 94% yield). ¹H NMR(400 MHz, DMSO-d6) δ 1.48-1.28 (m, 2H), 1.82 (d, J=13.9 Hz, 2H),1.97-2.14 (m, 1H), 2.35 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 2.88 (q, J=11.9Hz, 2H), 3.26 (d, J=12.8 Hz, 2H), 6.14 (s, 2H), 7.59 (s, 1H), 8.08 (s,1H), 8.24 (br. s, 1H), 8.54 (br. s, 1H), 11.78 (s, 1H).

EXAMPLE 28b tert-Butyl4-(2-((6-Acelylbenzo[d][1,3]dioxol-5-yl)amino)-2-oxoethyl)piperidine-1-carboxylate

Prepared in a similar manner as in Example 24b from1-(6-aminobenzo-[d][1,3]dioxol-5-yl)ethan-1-one (3.07 g, 17.13 mmol),2-(1-(tert-butoxycarbonyl)-piperidin-4-yl)acetic acid (5.0 g, 20.6mmol), HATU (9.78 g, 25.70 mmol), and DIEA (8.95 mL, 51.40 mmol) to givethe title compound as a yellowish oil (6.5 g, 16.1 mmol, 94% yield). ¹HNMR (400 MHz, DMSO-d6) δ 1.07 (qd, J=12.3, 4.2 Hz, 2H), 1.38 (s, 9H),1.65 (d, J=11.6 Hz, 2H), 1.87-1.99 (m, 1H), 2.30 (d, J=7.1 Hz, 2H), 2.57(s, 3H), 2.60-2.84 (m, 2H), 3.89 (d, J=13.2 Hz, 2H), 6.13 (s, 2H), 7.58(d, J=0.6 Hz, 1H), 8.11 (d, J=0.6 Hz, 1H), 11.80 (s, 1H). MS 305 (M+H⁺).

EXAMPLE 29 Synthesis ofN-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(3-methylbutanoyl)piperidin-4-yl)acetamide(198)

Prepared in a similar manner as in Example 24 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide HClsalt (Example 28a) (40 mg, 0.117 mmol) and isovaleryl chloride (16 uL,0.129 mmol) to afford the title compound as a colorless oil (43 mg, 96%yield). MS 389 (M+H⁺).

EXAMPLE 30 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(thiophene-2-carbonyl)piperidin-4-yl)acetamide(199)

Prepared in a similar manner as in Example 24 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide HClsalt (Example 28a) (42 mg, 0.123 mmol) and thiophene-2-carbonyl chloride(15 uL, 0.135 mmol) to afford the title compound as a white solid (39mg, 76% yield). MS 415 (M+H⁺).

EXAMPLE 31 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(furan-3-carbonyl)piperidin-4-yl)acetamide(200)

Prepared in a similar manner as in Example 18 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide HClsalt (Example 28a) (50 mg, 0.147 mmol) and 3-furoic acid (18 mg, 0.161mmol) to afford the title compound as a white powder (47.9 mg, 82%yield). MS 399 (M+H⁺).

EXAMPLE 32 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)acetamide(201)

Prepared in a similar manner as in Example 18 fromN-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-2-(piperidin-4-yl)acetamide HClsalt (Example 28a) (50 mg, 0.147 mmol) and1-methyl-1H-pyrazole-4-carboxylic acid (19 mg, 0.147 mmol) to afford thetitle compound as a white solid (40.5 mg, 67% yield). MS 413 (M+H⁺).

Compounds in Table 8 were prepared in a similar manner as in Example 2and/or Example 27 from the corresponding amine hydrochlorides describedherein (e.g. in Example 24a and 28a) and the corresponding commerciallyavailable carboxylic acids and/or acyl chlorides.

TABLE 8 Obs Mol hT2R54 Ion MS; IC50 SID Structure (M + 1) (uM) ¹H NMR(400 MHz) 193

389      0.017 (DMSO-d₆, 80° C.) δ 0.91 (d, J = 6.8 Hz, 6H), 1.25- 1.39(m, 2H), 1.64-1.67 (m, 1H), 1.82-1.85 (m, 1H), 1.91 (br. s, 1H),1.96-2.03 (m, 1H), 2.16-2.18 (m, 2H), 2.25-2.40 (m, 2H), 2.56 (s, 3H),2.80 (br. s, 2H), 3.88- 4.10 (m, 2H), 6.11 (s, 2H), 7.51 (s, 1H), 8.06(s, 1H) 11.61 (s, 1H). 194

399      0.006 (DMSO-d₆) δ 1.21-1.52 (m, 2H), 1.65-1.76 (m, 1H),1.80-1.89 (m, 1H), 1.95-2.06 (m, 1H), 2.27- 2.42 (m, 2H), 2.56 (s, 3H),2.98 (br s, 2H), 4.06-4.28 (m, 2H), 6.14 (s, 2H), 6.57 (br. s, 1H), 6.97(dd, J = 3.4, 0.7 Hz, 1H), 7.58 (s, 1H), 7.74 (br. s, 1H), 8.08 (s, 1H),11.79 (s, 1H). 195

415      0.008 (DMSO-^(d6)) δ 1.15-1.49 (m, 2H), 1.69-1.72 (m, 1H),1.84-1.87 (m, 1H), 2.02 (m, 1H), 2.35 (d, J = 6.8 Hz, 2H), 2.56 (s, 3H),2.85-3.01 (m, 2H), 4.12- 4.21 (m, 2H), 6.14 (s, 2H), 7.05 (t, J = 4.4Hz, 1H), 7.36 (dt, J = 3.7, 0.8 Hz, 1H), 7.58 (s, 1H), 7.71 (d, J = 4.8Hz, 1H), 8.06 (s, 1H), 11.78 (s, 1H). 196

399      0.184 (DMSO-_(d6)) δ 1.24-1.48 (m, 2H), 1.66-1.69 (m, 1H),1.82-1.86 (m, 1H), 1.97 (m, 1H), 2.32 (m, 2H), 2.56 (s, 3H), 2.83- 3.08(m, 2H), 3.85-4.26 (m, 2H), 6.15 (s, 2H), 6.62 (s, 1H), 7.58 (s, 1H),7.69 (br. s, 1H), 8.00 (s, 1H), 8.05 (br. s, 1H), 11.76 (br. s, 1H). 197

399      0.006 (DMSO-d₆) δ 1.21-1.26 (m, 2H), 1.74-1.77 (m, 2H),2.04-2.12 (m, 1H), 2.35 (d, J = 7.2 Hz, 2H), 2.57 (s, 3H), 2.98 (br. s,2H), 4.29 (br. s, 2H), 6.14 (s, 2H), 6.60 (dd, J = 3.5, 1.8 Hz, 1H),6.93 (dd, J = 3.5, 0.8 Hz, 1H), 7.58 (s, 1H), 7.81 (dd, J = 1.8, 0.8 Hz,1H), 8.11 (s, 1H), 11.81 (s, 1H). 198

389      0.045 (DMSO-d₆) δ 0.89 (d, J = 6.4 Hz, 6H), 0.98- 1.23 (m, 3H),1.68 (t, J = 15.2 Hz, 2H), 1.90- 2.04 (m, 1H), 2.17 (d, J = 7.2 Hz, 2H),2.31 (d, J = 13.6 Hz, 2H), 2.57 (s, 3H), 2.98 (t, J = 12.4 Hz, 2H), 3.88(d, J = 15.2 Hz, 1H), 4.39 (d, J = 13.6 Hz, 1H), 6.14 (s, 2H), 7.58 (s,1H), 8.11 (s, 1H), 11.80 (s, 1H). 199

415      0.012 (DMSO-d₆) δ 1.16- 1.28 (m, 2H), 1.76 (d, J = 12.8 Hz,2H), 2.08 (m, 1H), 2.36 (d, J = 7.2 Hz, 2H), 2.57 (s, 3H), 3.00 (br. s,2H), 4.24 (br. s, 2H), 6.14 (s, 2H), 7.11 (dd, J = 5.0, 3.6 Hz, 1H),7.36 (dd, J = 3.6, 1.0 Hz, 1H), 7.58 (s, 1H), 7.73 (dd, J = 5.0, 1.0 Hz,1H), 8.12 (s, 1H), 11.82 (s, 1H). 200

399      0.149 (DMSO-d₆) δ 1.16-1.23 (m, 2H), 1.73 (d, J = 11.6 Hz, 2H),2.06 (m, 1H), 2.34 (d, J = 7.2 Hz, 2H), 2.57 (s, 3H), 3.10 (br. s, 2H),4.39 (br. s, 2H), 6.14 (s, 2H), 6.63 (dd, J = 1.9, 0.8 Hz, 1H), 7.58 (s,1H), 7.73 (t, J = 1.6 Hz, 1H), 7.99 (dd, J = 1.6, 0.9 Hz, 1H), 8.12 (s,1H), 11.82 (s, 1H). 201

413      0.339 (400 MHz, DMSO-d₆) δ 1.15-1.27 (m, 2H), 1.74 (d, J = 12.8Hz, 2H), 2.06 (m, 1H), 2.34 (d, J = 7.2 Hz, 2H), 2.57 (s, 3H), 3.14 (m,1H), 3.62 (m, 1H), 3.84 (s, 3H), 4.21 (br. s, 2H), 6.14 (s, 2H), 7.58(s, 1H), 7.61 (d, J = 0.8 Hz, 1H), 8.01 (s, 1H), 8.12 (s, 1H), 11.82 (s,1H). 202

347      0.035 (DMSO-d₆, rotamers) δ 1.21-1.42 (m, 2H), 1.57- 1.83 (m,2H), 1.96 (s, 1.5H), 1.98 (s, 1.5H), 2.22-2.41 (m, 2H), 2.57 (s, 3H),2.67-2.72 (m, 1H), 2.87 (dd, J = 13.4, 9.9 Hz, 1H), 3.00 (ddd, J = 13.6,11.4, 3.0 Hz, 1H), 3.65-3.76 (m, 1H), 4.09-4.23 (m, 1H), 6.14 (s, 2H),7.58 (s, 1H), 8.07 (s, 0.5H), 8.11 (s, 0.5H), 11.76 (s, 0.5H), 11.81 (s,0.5H). 203

361      0.017 (DMSO-d₆, rotamers) δ 0.97 (t, J = 7.6 Hz, 3H), 1.10-1.43(m, 2H), 1.58- 1.80 (m, 2H), 2.25-2.43 (m, 5H), 2.56 (s, 3H), 2.83 (dd,J = 13.4, 10.4 Hz, 1H), 2.95-3.02 (m, 1H), 3.68-3.80 (m, 1H), 4.10-4.23(m, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.06 (s, 0.5H), 8.11 (s, 0.5H),11.74 (s, 0.5H), 11.80 (s, 0.5H). 204

375      0.016 (DMSO-d₆, rotamers) δ 0.86 (two t, J = 7.4 Hz, 3H),1.23-1.30 (m, 2H), 1.49 (q, J = 7.4 Hz, 2H), 1.59-1.91 (m, 2H), 2.22-2.40 (m, 5H), 2.57 (s, 3H), 2.84 (dd, J = 13.3, 10.3 Hz, 1H), 2.99 (ddd,J = 13.9, 11.2, 2.8 Hz, 1H), 3.70-3.80 (m, 1H), 4.11-4.23 (m, 1H), 6.14(s, 2H), 7.58 (s, 1H), 8.06 (s, 0.5H), 8.11 (s, 0.5H), 11.76 (s, 0.5H),11.81 (s, 0.5H). 205

375      0.012 (DMSO-d₆, rotamers) δ 0.95-0.99 (m, 6H), 1.24- 1.29 (m,2H), 1.61-1.80 (m, 2H), 2.21-2.38 (m, 3H), 2.56 (s, 3H), 2.80- 2.87 (m,2H), 3.02-3.07 (m, 1H), 3.76-3.91 (m, 1H), 4.21 (d, J = 9.2 Hz, 1H),6.14 (s, 2H), 7.58 (s, 1H), 8.05 (s, 0.5H), 8.11 (s, 0.5H), 11.75 (s,0.5H), 11.80 (s, 0.5H). 206

389      0.025 (DMSO-d₆, rotamers) δ 0.87 (two d, J = 15.9 Hz, 6H),1.06-1.41 (m, 2H), 1.54-1.70 (m, 1H), 1.74-1.85 (m, 2H), 1.88-2.06 (m,1H), 2.05-2.50 (m, 4.5H), 2.56 (s, 3H), 2.59-2.70 (m, 0.5H), 2.78-2.89(m, 0.5H), 2.94-3.05 (m, 0.5H), 3.68-3.84 (m, 1H), 4.11-4.26 (m, 1H),6.14 (s, 2H), 7.58 (s, 1H), 8.07 (s, 0.5H), 8.11 (s, 0.5H), 11.77 (s,0.5H), 11.81 (s, 0.5H). 207

403      0.36 (DMSO-d₆, rotamers) δ 0.94 (s, 4.5H), 0.97 (s, 4.5H),1.09-1.31 (m, 2H), 1.60-1.91 (m, 3H), 2.17- 2.46 (m, 4H), 2.57 (s, 3H),2.84 (dd, J = 13.4, 10.2 Hz, 1H), 3.01 (ddd, J = 13.7, 11.5, 2.6 Hz,1H), 3.84 (dd, J = 29.6, 13.5 Hz, 1H), 4.24 (t, J = 15.2 Hz, 1H), 6.14(s, 2H), 7.58 (s, 1H), 8.07 (s, 0.5H), 8.12 (s, 0.5H), 11.76 (s, 0.5H),11.82 (s, 0.5H). 208

389      0.17 (DMSO-d₆, rotamers) δ 0.75-0.82 (m, 3H), 0.93- 0.97 (m,3H), 1.23-1.31 (m, 2H), 1.50-1.57 (m, 3H), 2.24-2.39 (m, 3H), 2.56 (s,3H), 2.80-2.87 (m, 1H), 3.04-3.07 (m, 1H), 3.80-3.94 (m, 1H), 4.17-4.26(m, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.06 (s, 0.5H), 8.12 (s, 0.5H),11.72 (s, 0.5H), 11.81 (s, 0.5H). 209

403      0.056 (DMSO-d₆, rotamers) δ 1.24-1.43 (m, 2H), 1.60- 1.67 (m,2H), 1.77-1.86 (m, 4H), 1.98 (m, 1H), 2.22-2.39 (m, 2H), 2.56 (s, 3H),2.84-2.89 (m, 1H), 2.97-3.09 (m, 1H), 3.65-3.92 (m, 3H), 4.08- 4.18 (m,1H), 4.58-4.66 (m, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.07 (s, 0.5H), 8.11(s, 0.5H), 11.77 (s, 0.5H), 11.80 (s, 0.5H). 210

403      1.34 (DMSO-d₆, rotamers) δ 1.24-1.29 (m, 2H), 1.64- 2.07 (m,5H), 2.26-2.45 (m, 3H), 2.57 (s, 3H), 2.84 (dd, J = 13.4, 10.3 Hz, 1H),3.00-3.08 (m, 1H), 3.59-3.72 (m, 4H), 3.78-3.94 (m, 1H), 4.18- 4.21 (m,1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.05 (s, 0.5H), 8.11 (s, 0.5H), 11.74(s, 0.5H), 11.80 (s, 0.5H). 211

417      0.018 (DMSO-d₆, rotamers) δ 1.23-1.29 (m, 2H), 1.40- 1.66 (m,6H), 1.77-1.81 (m, 2H), 1.94 (m, 1H), 2.22-2.36 (m, 2H), 2.57 (s, 1.5H),2.57 (s, 1.5H), 2.81-2.89 (m, 1H), 2.95- 3.07 (m, 1H), 3.72-4.21 (m,3H), 6.14 (s, 2H), 7.58 (s, 0.5H), 7.59 (s, 0.5H), 8.09-8.15 (three s,1H), 11.77-11.88 (three s, 1H). 212

390    >1 (DMSO-d₆, rotamers) δ 1.23-1.45 (m, 2H), 1.60- 1.65 (m, 1H),1.76-1.84 (m, 1H), 1.96 (m, 1H), 2.07 (s, 3H), 2.16 (s, 3H), 2.26-2.33(m, 2H), 2.56 (s, 1.5H), 2.57 (s, 1.5H), 2.67-2.75 (m, 1H), 2.86 (dd, J= 13.1, 9.9 Hz, 0.5H), 2.96-3.00 (m, 2H), 3.07-3.10 (m, 0.5H), 3.84-3.94(m, 1H), 4.02- 4.05 (m, 0.5H), 4.14- 4.18 (m, 0.5H), 6.14 (s, 2H), 7.58(s, 0.5H), 7.59 (s, 0.5H), 8.11 (s, 0.5H), 8.13 (s, 0.5H), 11.81 (s,0.5H), 11.83 (s, 0.5H). 213

377      0.05 ¹H NMR (400 MHz, DMSO-d₆) δ 1.09-1.39 (m, 7H), 1.58-1.63(m, 1H), 2.23-2.37 (m, 2H), 2.57 (s, 3H), 2.85 (ddd, J = 13.4, 11.0, 3.2Hz, 1H), 3.75-3.86 (m, 2H), 4.00 (q, J = 7.0 Hz, 2H), 6.14 (s, 2H), 7.58(s, 1H), 8.10 (s, 1H), 11.79 (s, 1H). 214

391      0.32 (DMSO-d₆) δ 0.80-0.89 (m, 3H), 1.11-1.38 (m, 4H),1.52-1.64 (m, 2H), 1.89 (m, 1H), 2.24-2.36 (m, 3H), 2.57 (s, 3H), 2.85(ddd, J = 13.6, 10.9, 3.1 Hz, 1H), 3.78- 3.92 (m, 4H), 6.14 (s, 2H),7.58 (s, 1H), 8.10 (s, 1H), 11.80 (s, 1H). 215

391      0.16 (DMSO-d₆) δ 1.14 (m, 6H), 1.26-1.36 (m, 1H), 1.57-1.62 (m,1H), 1.74- 1.79 (m, 1H), 1.89 (m, 1H), 2.23-2.36 (m, 3H), 2.57 (s, 3H),2.67-2.87 (m, 2H), 3.76 (m, 2H), 4.70-4.75 (m, 1H), 6.14 (s, 2H), 7.58(s, 1H), 8.10 (s, 1H), 11.80 (s, 1H). 216

409      0.08 (DMSO-d₆, rotamers) δ 1.29-1.35 (m, 1H), 1.46 (br.s, 1H),1.58 (br.s, 0.5H), 1.72 (br.s, 0.5H), 1.83-1.86 (m, 1H), 2.00 (br.s,1H), 2.19-2.40 (m, 2H), 2.56 (s, 3H), 2.72- 3.01 (m, 2H), 3.46 (br.s,0.5H), 3.57 (br.s, 0.5H), 4.30 (br.s, 1H), 6.14 (s, 2H), 7.33-7.43 (m,5H), 7.57 (s, 1H), 7.89 (br.s, 0.5H), 8.13 (br.s, 0.5H), 11.67 (br.s,0.5H), 11.83 (br.s, 0.5H). 217

425      0.48 (DMSO-d₆, rotamers) δ 1.23-1.32 (m, 1H), 1.36- 1.44 (m,1H), 1.61 (m, 1H), 1.79-1.81 (m, 1H), 1.97 (m, 1H), 2.28 (m, 2H), 2.56(s, 3H), 2.72- 2.78 (m, 1H), 2.91 (m, 1H), 3.42 (m, 1H), 4.27 (m, 1H),6.14 (s, 2H), 6.80 (m, 2H), 7.05 (br.s, 1H), 7.15 (br.s, 1H), 7.57 (s,1H), 7.89 (br.s, 0.5H), 7.12 (br.s, 0.5H), 9.71 (br.s, 1H), 11.69 (br.s,0.5H), 11.82 (br.s, 0.5H). 218

425    >1 (DMSO-d₆, rotamers) δ 1.23-1.33 (m, 1H), 1.40 (m, 1H),1.59-1.69 (m, 1H), 1.82-1.84 (m, 1H), 1.97 (m, 1H), 2.29 (m, 2H), 2.56(s, 3H), 2.84- 2.97 (m, 2H), 3.49 (br.s, 0.5H), 3.59 (br.s, 0.5H), 4.28(m, 1H), 6.14 (s, 2H), 6.69-6.81 (m, 3H), 7.05-7.24 (m, 1H), 7.57 (s,1H), 7.93 (br.s, 0.5H), 8.13 (br.s, 0.5H), 9.58 (br.s, 0.5H), 9.64(br.s, 0.5H), 11.69 (br.s, 0.5H), 11.83 (br.s, 0.5H). 219

425      1.46 (DMSO-d₆) δ 1.23-1.33 (m, 1H), 1.38-1.47 (m, 1H), 1.64 (m,1H), 1.82- 1.85 (m, 1H), 1.97 (m, 1H), 2.29 (m, 2H), 2.56 (s, 3H), 2.74(br.s, 1H), 2.91 (br.s, 1H), 3.96 (br.s, 2H), 6.14 (s, 2H), 6.73 (m,2H), 7.19 (d, J = 8.4 Hz, 2H), 7.58 (s, 1H), 8.05 (br.s, 1H), 9.77 (s,1H), 11.78 (s, 1H). 220

399    ~0.01 (DMSO-d₆) δ 1.21-1.52 (m, 2H), 1.65-1.76 (m, 1H), 1.80-1.89(m, 1H), 1.95-2.06 (m, 1H), 2.27- 2.42 (m, 2H), 2.56 (s, 3H), 2.98 (brs, 2H), 4.06-4.28 (m, 2H), 6.14 (s, 2H), 6.57 (br. s, 1H), 6.97 (dd, J =3.4, 0.7 Hz, 1H), 7.58 (s, 1H), 7.74 (br. s, 1H), 8.08 (s, 1H), 11.79(s, 1H). 221

413      0.060 (DMSO-d₆) δ 1.29-1.45 (m, 2H), 1.62-1.67 (m, 1H),1.80-1.83 (m, 1H), 2.30-2.33 (m, 3H), 2.54 (s, 3H), 3.09-3.15 (m, 2H),3.56-3.63 (m, 2H), 3.79 (s, 3H), 6.12 (s, 2H), 7.60 (s, 1H), 7.98 (s,1H), 8.06 (s, 1H), 8.14 (br.s, 1H), 11.76 (br.s, 1H). 222

383      0.06 (DMSO-d₆) δ 1.12-1.29 (m, 2H), 1.49-1.52 (m, 1H),1.71-1.77 (m, 1H), 2.05 (m, 1H), 2.30-2.42 (m, 2H), 2.57 (s, 3H),2.67-2.73 (m, 2H), 2.83 (s, 3H), 3.40-3.43 (m, 1H), 3.51 (dd, J = 11.6,3.2 Hz, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.09 (s, 1H), 11.79 (s, 1H).223

397      0.04 (DMSO-d₆) δ 1.19 (t, J = 7.2 Hz, 3H), 1.42- 1.49 (m, 2H),1.67-1.78 (m, 2H), 2.28-2.41 (m, 3H), 2.57 (s, 3H), 2.62 (dd, J = 11.8,9.9 Hz, 1H), 2.80 (td, J = 11.5, 2.6 Hz, 1H), 3.01 (q, J = 7.4, 2H),3.44-3.47 (m, 1H), 3.55 (dd, J = 12.2, 3.6 Hz, 1H), 6.14 (s, 2H), 7.58(s, 1H), 8.09 (s, 1H), 11.86 (s, 1H). 224

411      0.04 (DMSO-d₆) δ 0.97 (t, J = 7.4 Hz, 3H), 1.11- 1.28 (m, 2H),1.43- 1.51 (m, 2H), 1.62- 1.77 (m, 2H), 2.28- 2.41 (m, 3H), 2.57 (s,3H), 2.60-2.63 (m, 1H), 2.77 (dd, J = 11.4, 2.0 Hz, 1H), 2.91-3.02 (m,2H), 3.43-3.46 (m, 1H), 3.54 (dd, J = 11.2, 1.8 Hz, 1H), 6.14 (s, 2H),7.58 (s, 1H), 8.09 (s, 1H), 11.79 (s, 1H). 225

425      0.07 (DMSO-d₆) δ 0.89 (t, J = 7.6 Hz, 3H), 1.11- 1.29 (m, 2H),1.38 (dq, J = 14.6, 7.3 Hz, 2H), 1.46-1.48 (m, 1H), 1.58-1.73 (m, 3H),2.28-2.41 (m, 3H), 2.58 (s, 3H), 2.61 (dd, J = 11.5, 10.1 Hz, 1H), 2.79(td, J = 11.4, 10.8, 2.3 Hz, 1H), 2.97-3.01 (m, 2H), 3.44-3.47 (m, 1H),3.54 (dd, J = 11.6, 3.5 Hz, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.09 (s,1H), 11.80 (s, 1H). 226

425      0.16 (DMSO-d₆) δ 1.01 (d, J = 6.8 Hz, 6H), 1.13- 1.19 (m, 1H),1.23- 1.30 (m, 1H), 1.68-1.77 (m, 2H), 1.99-2.13 (m, 2H), 2.29-2.41 (m,2H), 2.54-2.59 (m, 4H), 2.75 (td, J = 11.2, 10.8, 2.2 Hz, 1H), 2.86 (d,J = 6.4 Hz, 2H), 6.14 (s, 2H), 7.58 (s, 1H), 8.09 (s, 1H), 11.79 (s,1H). 227

435      0.13 (DMSO-d₆) δ 1.08-1.10 (m, 1H), 1.42-1.48 (m, 1H),1.67-1.70 (m, 2H), 1.99 (m, 1H), 2.26-2.43 (m, 3H), 2.55 (s, 3H),2.59-2.62 (m, 1H), 3.46- 3.49 (m, 1H), 3.56-3.59 (m, 1H), 6.14 (s, 2H),6.73 (dd, J = 3.5, 1.8 Hz, 1H), 7.17 (dd, J = 3.5, 0.9 Hz, 1H), 7.58 (s,1H), 8.02 (dd, J = 1.8, 0.9 Hz, 1H), 8.08 (s, 1H), 11.76 (s, 1H). 228

443      0.02 (DMSO-d₆) δ 1.23-1.47 (m, 2H), 1.68-1.72 (m, 1H),1.82-1.86 (m, 1H), 2.04 (m, 1H), 2.35 (d, J = 7.2 Hz, 2H), 2.56 (s, 3H),2.94 (br.s, 2H), 3.23 (s, 3H), 4.11-4.14 (m, 1H), 4.19-4.23 (m, 1H),4.34 (br.s, 2H), 6.14 (s, 2H), 6.15 (br.s, 1H), 6.90 (d, J = 3.2 Hz,1H), 7.58 (s, 1H), 8.08 (s, 1H), 11.79 (s, 1H). 229

391      0.22 (DMSO-d₆, rotamers) δ 0.85-0.92 (two d, J = 6.4 Hz, 6H),1.94-2.02 (m, 1H), 2.12-2.27 (m, 2H), 2.57 (s, 3H), 2.63-2.71 (m, 2H),2.90-2.96 (m, 1H), 3.08-3.15 (m, 1H), 3.70-3.92 (m, 3H), 4.17- 4.21 (m,1H), 4.31-4.35 (m, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.10 (s, 0.5H), 8.12(s, 0.5H), 11.83 (s, 0.5H), 11.86 (s, 0.5H). 230

379      0.16 (DMSO-d₆) δ 1.18 (t, J = 7.2 Hz, 3H), 2.57 (s, 3H),2.63-2.68 (m, 2H), 3.43 (td, J = 11.6, 2.8 Hz, 2H), 3.73-3.92 (m, 5H),4.02-4.07 (m, 2H), 6.14 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.85 (s,1H). 231

401      0.24 (DMSO-d₆) δ 2.57 (s, 3H), 2.71 (dd, J = 15.2, 4.3 Hz, 2H),3.48-3.55 (m, 2H), 3.85-3.91 (m, 3H), 4.13-4.20 (m, 1H), 4.33 (d, J =13.6 Hz, 1H), 6.14 (s, 2H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H), 6.98-7.09(m, 1H), 7.58 (s, 1H), 7.84 (dd, J = 1.7, 0.7 Hz, 1H), 8.11 (s, 1H),11.86 (s, 1H). 232

347    >1 (DMSO-d₆) δ 0.95-1.24 (m, 2H), 1.60-1.74 (m, 2H), 1.9-2.06 (m,4H), 2.30 (d, J = 7.1 Hz, 2H), 2.57 (s, 3H), 3.00 (ddd, J = 13.5, 12.2,2.7 Hz, 1H), 3.27-3.43 (m, 1H), 3.72-3.83 (m, 1H), 4.33 (dm, J = 13.1Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.81 (s, 1H). 233

361      0.086 (DMSO-d₆) δ 0.97 (t, J = 7.4 Hz, 3H), 1.00- 1.21 (m, 2H),1.68 (t, J = 14.8 Hz, 2H), 1.93- 2.06 (m, 1H), 2.25-2.34 (m, 4H),2.50-2.56 (m, 1H), 2.57 (s, 3H), 2.91- 3.04 (m, 1H), 3.82 (d, J = 13.7Hz, 1H), 4.35 (d, J = 13.0 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s,1H), 11.81 (s, 1H). 234

375    >1 (DMSO-d₆) δ 0.87 (t, J = 7.4 Hz, 3H), 0.92- 1.23 (m, 2H), 1.49(h, J = 7.4 Hz, 2H), 1.68 (t, J = 15.3 Hz, 2H), 1.94-2.06 (m, 1H),2.22-2.28 (m, 2H), 2.30 (d, J = 7.0 Hz, 2H), 2.52-2.56 (m, 1H), 2.57 (s,3H), 2.98 (t, J = 13.0 Hz, 1H), 3.84 (d, J = 13.8 Hz, 1H), 4.36 (d, J =13.2 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.80 (s, 1H).235

389      0.077 (DMSO-d₆) δ 0.87 (t, J = 7.3 Hz, 3H), 0.95- 1.21 (m, 2H),1.23-1.33 (m, 2H), 1.39-1.51 (m, 2H), 1.62-1.74 (m, 2H), 1.93-2.06 (m,1H), 2.23-2.34 (m, 4H), 2.47- 2.55 (m, 1H), 2.57 (s, 3H), 2.92-3.03 (m,1H), 3.84 (d, J = 13.6 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 6.13 (s, 2H),7.58 (s, 1H), 8.11 (s, 1H), 11.80 (s, 1H). 236

375    >1 (DMSO-d₆) δ 0.93-1.21 (m, 8H), 1.61-1.78 (m, 2H), 1.94-2.07(m, 1H), 2.31 (d, J = 7.1 Hz, 2H), 2.50-2.56 (m, 1H), 2.57 (s, 3H),2.79-2.90 (m, 1H), 3.00 (t, J = 12.3 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H),4.37 (d, J = 13.0 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H),11.80 (s, 1H). 237

389      0.19 (DMSO-d₆) δ 0.99-1.15 (m, 2H), 1.17 (s, 9H), 1.69 (d, J =12.9 Hz, 2H), 1.96-2.08 (m, 1H), 2.31 (d, J = 7.1 Hz, 2H), 2.57 (s, 3H),2.77 (t, J = 12.7 Hz, 2H), 4.25 (d, J = 13.4 Hz, 2H), 6.13 (s, 2H), 7.58(s, 1H), 8.11 (s, 1H), 11.80 (s, 1H). 238

373      0.47 ¹H NMR (400 MHz, DMSO-d₆) δ 0.60-0.74 (m, 4H), 0.96-1.24(m, 2H), 1.60-1.80 (m, 2H), 1.89-2.10 (m, 2H), 2.32 (d, J = 7.1 Hz, 2H),2.52-2.62 (m, 4H), 3.07 (t, J = 13.2 Hz, 1H), 4.17-4.38 (m, 2H), 6.14(s, 2H), 7.58 (s, 1H), 8.12 (s, 1H), 11.81 (s, 1H). 239

415    >1 (DMSO-d₆) δ 0.92-1.38 (m, 7.5H), 1.54-1.77 (m, 7.5H),1.94-2.06 (m, 1H), 2.30 (d, J = 7.1 Hz, 2H), 2.50-2.56 (m, 1H), 2.57 (s,3H), 2.99 (t, J = 12.8 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 4.36 (d, J =13.1 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.80 (s, 1H).240

377      0.034 (DMSO-d₆) δ 1.04-1.14 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H),1.66 (br d, J = 13.2 Hz, 2H), 1.89-1.99 (m, 1H), 2.31 (d, J = 7.1 Hz,2H), 2.57 (s, 3H), 2.69-2.87 (m, 2H), 3.95 (br d, J = 13.2 Hz, 2H), 4.04(q, J = 7.2 Hz, 2H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.81 (s,1H). 241

391      0.072 (DMSO-d₆) δ 0.88 (t, J = 7.4 Hz, 3H), 1.04- 1.16 (m, 2H),1.51-1.61 (m, 2H), 1.62-1.70 (m, 2H), 1.89-2.00 (m, 1H), 2.31 (d, J =7.1 Hz, 2H), 2.56 (s, 3H), 2.68- 2.86 (m, 2H), 3.87-4.00 (m, 4H), 6.13(s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.80 (s, 1H). 242

403      0.068 (DMSO-d₆) δ 0.96-1.25 (m, 2H), 1.63-1.74 (m, 2H),1.74-1.89 (m, 2H), 1.89-2.07 (m, 3H), 2.31 (d, J = 7.1 Hz, 2H), 2.51-2.61 (m, 1H), 2.57 (s, 3H), 2.92-306 (m, 1H), 3.65-3.81 (m, 2H), 3.96(br d, J = 13.6 Hz, 1H), 4.30 (br d, J = 12.8 Hz, 1H), 4.59-4.66 (m,1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.11 (two s, 1H), 11.79 (s, 0.5H),11.81 (s, 0.5H). 243

417      0.096 (DMSO-d₆), rotamers) δ 0.93-1.08 (m, 1H), 1.12- 1.23 (m,1H), 1.37-1.60 (m, 4H), 1.69 (br s, 2H), 1.74-1.82 (m, 1H), 1.91- 2.05(m, 1H), 2.30 (d, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.97 (q, J = 12.8, 12.3Hz, 1H), 3.42-3.50 (m, 1H), 3.84 (br d, J = 11.5 Hz, 1H), 3.94 (br d, J= 13.2 Hz, 1H), 4.09 (br d, J = 9.6 Hz, 1H), 4.30 (br s, 1H), 6.13 (s,2H), 7.58 (s, 1H), 8.10-8.12 (two s, 1H), 11.77-11.83 (two s, 1H). 244

410      0.051 (DMSO-d6) δ 1.20-1.28 (m, 2H), 1.62-1.65 (m, 1H),1.77-1.80 (m, 1H), 2.06 (m, 1H), 2.34 (d, J = 6.5 Hz, 2H), 2.57 (s, 3H),2.71-2.84 (m, 1H), 3.07-3.13 (m, 1H), 3.49- 3.52 (m, 1H), 4.45 (m, 1H),6.13 (s, 2H), 7.47 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.58 (s, 1H), 7.81(dt, J = 7.8, 1.8 Hz, 1H), 8.11 (s, 1H), 8.59 (dd, J = 2.2, 0.9 Hz, 1H),8.63 (dd, J = 4.9, 1.7 Hz, 1H), 11.82 (s, 1H). 245

453      0.044 (DMSO-d₆) δ 1.22 (br s, 2H), 1.63 (br s, 1H), 1.75 (br s,1H), 1.97-2.12 (m, 1H), 2.34 (d, J = 7.2 Hz, 2H), 2.52-2.54 (m, 1H),2.57 (s, 3H), 2.78 (br s, 1H), 3.04 (br s, 1H), 3.28-3.30 (m, 3H), 3.53(br s, 1H), 4.37 (s, 2H), 6.13 (s, 2H), 7.24-7.34 (m, 2H), 7.31-7.46 (m,2H), 7.57 (s, 1H), 8.11 (s, 1H), 11.81 (s, 1H). 246

400      2.31 (DMSO-d₆) δ 1.22-1.27 (m, 2H), 1.69-1.81 (m, 2H), 2.09 (m,1H), 2.34 (d, J = 6.4 Hz, 2H), 2.57 (s, 3H), 2.85 (td, J = 12.7, 2.9 Hz,1H), 3.10- 3.17 (m, 1H), 3.82 (d, J = 13.5 Hz, 1H), 4.45 (d, J = 13.1Hz, 1H), 6.13 (d, J = 0.7 Hz, 2H), 6.80 (dd, J = 1.7, 0.6 Hz, 1H), 7.58(s, 1H), 8.11 (s, 1H), 9.07 (dd, J = 1.7, 0.7 Hz, 1H), 11.81 (s, 1H).247

423      0.49 (DMSO-d₆) δ 0.9-1.08 (m, 2H), 1.64 (t, J = 16.3 Hz, 2H),1.91-2.05 (m, 1H), 2.26 (d, J = 7.1 Hz, 2H), 2.51-2.60 (m, 4H), 2.98 (t,J = 12.7 Hz, 1H), 3.69 (s, 2H), 3.93 (d, J = 13.5 Hz, 1H), 4.36 (d, J =13.1 Hz, 1H), 6.13 (s, 2H), 7.18-7.33 (m, 5H), 7.57 (s, 1H), 8.09 (s,1H), 11.77 (s, 1H). 248

441      0.42 (DMSO-d₆) δ 0.98-1.21 (m, 2H), 1.69 (t, J = 11.4 Hz, 2H),1.95-2.08 (m, 1H), 2.31 (d, J = 7.1 Hz, 2H), 2.52-2.64 (m, 4H),2.99-3.11 (m, 1H), 3.68-3.78 (m, 2H), 3.95 (d, J = 13.6 Hz, 1H), 4.35(d, J = 13.0 Hz, 1H), 6.13 (s, 2H), 7.10- 7.16 (m, 2H), 7.18-7.35 (m,2H), 7.57 (s, 1H), 8.11 (s, 1H), 11.82 (s, 1H). 249

441      2.54 (DMSO-d₆) δ 0.95-1.29 (m, 2H), 1.57-1.74 (m, 2H),1.91-2.07 (m, 1H), 2.27 (d, J = 7.0 Hz, 2H), 2.52-2.64 (m, 4H), 3.00 (brt, J = 13.7 Hz, 1H), 3.72 (s, 2H), 3.93 (br d, J = 17.6, 1H), 4.36 (brd, J = 13.6, 1H), 6.13 (s, 2H), 6.98-7.09 (m, 3H), 7.26-7.38 (m, 1H),7.56 (s, 1H), 8.10 (s, 1H), 11.80 (s, 1H). 250

424      0.76 (DMSO-d₆) δ 0.96-1.17 (m, 2H), 1.64-1.74 (m, 2H),1.92-2.06 (m, 1H), 2.30 (d, J = 7.0 Hz, 2H), 2.52-2.64 (m, 4H), 2.97-3.10 (m, 1H), 3.74 (s, 2H), 3.98 (br d, J = 12.8 Hz, 1H), 4.35 (br d, J= 13.3 Hz, 1H), 6.13 (s, 2H), 7.32 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.58(s, 1H), 7.60 (dt, J = 8.0, 2.0 Hz, 1H), 8.11 (s, 1H), 8.38-8.45 (m,2H), 11.80 (s, 1H). 251

424      0.58 (DMSO-d₆) δ 0.99-1.12 (m, 2H), 1.67 (d, J = 12.8 Hz, 2H),1.94-2.06 (m, 1H), 2.29 (d, J = 7.1 Hz, 2H), 2.54-2.63 (m, 1H), 2.57 (s,3H), 2.96- 3.07 (m, 1H), 3.75 (s, 2H), 3.91 (d, J = 13.5 Hz, 1H), 4.35(d, J = 13.1 Hz, 1H), 6.13 (s, 2H), 7.19-7.26 (m, 2H), 7.58 (s, 1H),8.10 (s, 1H), 8.43-8.51 (m, 2H), 11.79 (s, 1H). 252

439      1.09 (DMSO-d₆) δ 0.92-1.09 (m, 2H), 1.65 (t, J = 14.4 Hz, 2H),1.92-2.06 (m, 1H), 2.27 (d, J = 7.0 Hz, 2H), 2.52-2.56 (m, 4H),2.94-3.05 (m, 1H), 3.46-3.64 (m, 2H), 3.92 (br d, J = 13.7 Hz, 1H), 4.36(br d, J = 13.1 Hz, 1H), 6.13 (s, 2H), 6.68- 6.82 (m, 2H), 6.99-7.08 (m,2H), 7.57 (s, 1H), 8.10 (s, 1H), 9.54 (s, 1H), 11.78 (s, 1H). 253

439      0.75 ¹H NMR (400 MHz, DMSO-d₆) δ 0.89-1.10 (m, 2H), 1.63 (dd, J= 23.3, 13.2 Hz, 2H), 1.91-2.03 (m, 1H), 2.26 (d, J = 7.1 Hz, 2H),2.53-2.60 (m, 4H), 2.90-3.01 (m, 1H), 3.53-2.65 (m, 2H), 3.88 (br d, J =13.6 Hz, 1H), 4.36 (br d, J = 13.3 Hz, 1H), 6.13 (s, 2H), 6.56- 6.66 (m,3H), 7.03-7.12 (m, 1H), 7.57 (s, 1H), 8.09 (s, 1H), 9.31 (s, 1H), 11.77(s, 1H). 254

439      0.32 (DMSO-d₆) δ 0.88-1.08 (m, 2H), 1.63 (br t, J = 15.2 Hz,2H), 1.89-2.03 (m, 1H), 2.25 (d, J = 7.l Hz, 2H), 2.51-2.60 (m, 4H),2.95 (br t, J = 13.6 Hz, 1H), 3.54 (s, 2H), 3.90 (br d, J = 14.0 Hz,1H), 4.35 (br d, J = 13.4 Hz, 1H), 6.12 (s, 2H), 6.57-6.72 (m, 2H),6.96- 7.04 (m, 2H), 7.55 (s, 1H), 8.09 (s, 1H), 9.25 (s, 1H), 11.78 (s,1H). 255

453      1.30 (DMSO-d₆) δ 0.96-1.12 (m, 2H), 1.56-1.73 (m, 2H),1.90-2.06 (m, 1H), 2.28 (d, J = 7.0 Hz, 2H), 2.51-2.63 (m, 4H), 2.94-3.06 (m, 1H), 3.49-3.65 (m, 2H), 3.75 (s, 3H), 3.88 (br d, J = 13.7 Hz,1H), 4.36 (br d, J = 13.2 Hz, 1H), 6.13 (s, 2H), 6.82-7.03 (m, 2H),7.05- 7.26 (m, 2H), 7.56 (s, 1H), 8.11 (s, 1H), 11.81 (s, 1H). 256

453      0.38 (DMSO-d₆) δ 0.89-1.10 (m, 2H), 1.63 (br t, J = 15.6 Hz,2H), 1.90-2.06 (m, 1H), 2.26 (d, J = 7.0 Hz, 2H), 2.51-2.60 (m, 4H),2.97 (td, J = 13.4, 2.9 Hz, 1H), 3.66 (s, 2H), 3.72 (s, 3H), 3.92 (br d,J = 14.0 Hz, 1H), 4.36 (br d, J = 10.3, 1H), 6.13 (s, 2H), 6.74-6.82 (m,3H), 7.15-7.25 (m, 1H), 7.56 (s, 1H), 8.10 (s, 1H), 11.79 (s, 1H). 257

453      1.57 (DMSO-d₆) δ 0.90-1.09 (m, 2H), 1.64 (br t, J = 14.9 Hz,2H), 1.90-2.06 (m, 1H), 2.26 (d, J = 7.1 Hz, 2H), 2.51-2.60 (m, 4H),2.90-3.02 (m, 1H), 3.61 (s, 2H), 3.72 (s, 3H), 3.92 (br d, J = 14.4 Hz,1H), 4.35 (br d, J = 13.0 Hz, 1H), 6.13 (s, 2H), 6.81-6.90 (m, 2H),7.08-7.17 (m, 2H), 7.57 (s, 1H), 8.10 (s, 1H), 11.78 (s, 1H). 258

333      0.928 (DMSO-d₆, rotamers) δ 1.48-1.72 (m, 1H), 1.91 (two s,3H), 1.93-2.12 (m, 1H), 2.43-2.68 (m, 6H), 2.87-2.95 (m, 0.5H),3.05-3.24 (m, 1H), 3.33-3.69 (m, 2.5H), 6.14 (s, 2H), 7.58 (s, 1H), 8.08(s, 0.5H), 8.09 (s, 0.5H) 11.78 (s, 0.5H), 11.79 (s, 0.5H). 259

347      2.596 (DMSO-d₆, rotamers) δ 0.96 (two t, J = 7.4 Hz, 3H),1.45-1.71 (m, 1H), 1.92-2.12 (m, 1H), 2.14- 2.26 (m, 2H), 2.42-2.65 (m,6H), 2.93 (dd, J = 11.6, 6.9 Hz, 0.5H), 3.09 (dd, J = 10.0, 7.7 Hz,0.5H), 3.13-3.25 (m, 0.5H), 3.31-3.67 (m, 2.5H), 6.14 (s, 2H), 7.58 (s,1H), 8.08 (s, 0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.79 (s, 0.5H).260

361      0.844 (DMSO-d₆, rotamers) δ 0.87 (two s, J = 7.4, 3H),1.43-1.70 (m, 3H), 1.92- 2.12 (m, 1H), 2.14-2.26 (m, 2H), 2.36-2.65 (m,6H), 2.93 (dd, J = 11.6, 6.9 Hz, 0.5H), 3.09 (dd, J = 10.0, 7.7 Hz,0.5H), 3.13-3.25 (m, 0.5H), 3.27- 3.67 (m, 2.5H), 6.14 (s, 2H), 7.58 (s,1H), 8.08 (s, 0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.79 (s, 0.5H).261

361      0.958 (DMSO-d₆, rotamers) δ 0.95-1.02 (m, 6H), 1.48- 1.70 (m,1H), 1.93-2.15 (m, 1H), 2.43-2.68 (m, 6H), 2.87-2.97 (m, 0.5H),3.11-3.26 (m, 1H), 3.38-3.49 (m, 1H), 3.51- 3.63 (m, 1H), 3.71 (dd, J =10.1, 6.9 Hz, 0.5H), 6.14 (s, 2H), 7.58 (s, 1H), 8.08 (s, 0.5H), 8.09(s, 0.5H) 11.77 (s, 0.5H), 11.79 (s, 0.5H). 262

375      0.29 (400 MHz, DMSO-d₆) δ 1.15 (s, 9H), 1.54 (br s, 2H), 1.99(br s, 2H), 2.56 (s, 3H), 2.80-3.96 (m, 5H), 6.14 (s, 2H), 7.58 (s, 1H),8.08 (s, 1H), 11.77 (s, 1H). 263

375      0.374 (DMSO-d₆, rotamers) δ 0.84-0.95 (m, 6H), 1.45- 1.70 (m,1H), 1.92-2.15 (m, 4H), 2.44-2.62 (m, 6H), 2.88-2.98 (m, 0.5H),3.05-3.25 (m, 1H), 3.34- 3.69 (m, 2.5H), 6.14 (s, 2H), 7.58 (s, 1H),8.08 (s, 0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.79 (s, 0.5H). 264

389      0.381 (DMSO-d₆, rotamers) δ 0.94-1.05 (two s, 9H), 1.45-1.70(m, 1H), 1.92- 2.14 (m, 3H), 2.39-2.63 (m, 5H), 2.93 (dd, J = 12.1, 6.6Hz, 0.5H), 3.06-3.26 (m, 1H), 3.34- 3.71 (m, 3.5H), 6.13 (s, 2H), 7.57(s, 1H), 8.08 (s, 0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.80 (s,0.5H). 265

359      0.682 (DMSO-d₆, rotamers) δ 0.63-0.76 (m, 4H), 1.48- 1.78 (m,2H), 1.94-2.06 (m, 1H), 2.06-2.16 (m, 1H), 2.51-2.67 (m, 5H), 2.89-2.98(m, 0.5H), 3.15-3.32 (m, 1H), 3.40- 3.62 (m, 1.5H), 3.73 (ddd, J = 9.9,8.1, 3.7 Hz, 0.5H), 3.86 (dd, J = 10.0, 7.1 Hz, 0.5H), 6.14 (s, 2H),7.58 (s, 1H), 8.07 (s, 0.5H), 8.09 (s, 0.5H), 11.79 (s, 1H). 266

387      0.506 (DMSO-d₆, rotamers) δ 1.45-1.80 (m, 10H), 1.92- 2.05 (m,0.5H), 2.03 2.13 (m, 0.5H), 2.42-2.64 (m, 5H), 2.72-2.86 (m, 1H), 2.93(dd, J = 11.7, 7.1 Hz, 0.5H), 3.11-3.26 (m, 1H), 3.37-3.49 (m, 1H),3.51-3.64 (m, 1H), 3.71 (dd, J = 10.1, 6.9 Hz, 0.5H), 6.14 (s, 2H), 7.58(s, 1H), 8.08 (s, 0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.79 (s,0.5H). 267

401      2.249 (DMSO-d₆, rotamers) δ 1.07-1.36 (m, 5H), 1.45- 1.57 (m,0.5H), 1.58- 1.74 (m, 6H), 1.91-2.04 (m, 0.5H), 2.03-2.11 (m, 0.5H),2.27-2.41 (m, 1H), 2.41-2.65 (m, 5H), 2.91 (dd, J = 11.7, 7.3 Hz, 0.5H),3.11-3.24 (m, 1H), 3.37-3.48 (m, 1H), 3.49-3.64 (m, 1H), 3.71 (dd, J =10.1. 6.9 Hz, 0.5H), 6.13-2.15 (two s, 2H), 7.58 (s, 1H), 8.07 (s,0.5H), 8.09 (s, 0.5H) 11.77 (s, 0.5H), 11.79 (s, 0.5H). 268

363      0.117 (DMSO-d₆) δ 1.12-1.21 (m, 3H), 1.48-1.66 (m, 2H),1.93-2.07 (m, 2H), 2.38-2.54 (m, 1H), 2.57 (s, 3H), 2.88-3.07 (m, 1H),3.15-3.43 (m, 2H), 3.48-3.57 (m, 1H), 4.01 (q, J = 7.2 Hz, 2H), 6.14 (s,1H), 7.58 (s, 1H), 8.08 (s, 1H), 11.78 (s, 1H). 269

377      0.103 (DMSO-d₆) δ 0.88 (two t, J = 7.4 Hz, 3H), 1.48- 1.64 (m,3H), 1.96-2.05 (m, 1H), 2.56 (s, 3H), 2.89-3.01 (m, 1H), 3.15- 3.33 (m,1H), 3.34-3.42 (m, 1H), 3.46-3.57 (m, 1H), 3.92 (t, J = 6.4 Hz, 2H),6.14 (s, 2H), 7.58 (s, 1H), 8.08 (s, 1H), 11.78 (s, 1H). 454

410      0.3 (DMSO-d₆) δ 1.11-1.33 (m, 2H), 1.62 (d, J = 12.8 Hz, 1H),1.78 (d, J = 12.8 Hz, 1H), 2.07 (m, 1H), 2.34 (dd, J = 7.1, 2.8 Hz, 2H),2.57 (s, 3H), 2.72-2.88 (m, 1H), 3.06 (t, J = 12.5 Hz, 1H), 3.36-3.50(m, 1H), 4.45 (d, J = 13.1 Hz, 1H), 6.13 (s, 2H), 7.27-7.43 (m, 2H),7.58 (s, 1H), 8.11 (s, 1H), 8.59-8.69 (m, 2H), 11.82 (s, 1H). 455

441      6.0 456

441      1.3 (DMSO-d₆) δ 1.23-1.45 (m, 2H), 1.63 (m, 1H), 1.83 (m, 1H),1.95 (m, 1H), 2.29 (d, J = 7.4 Hz, 2H), 2.56 (s, 3H), 2.72- 2.89 (m,2H), 3.97 (br.s, 2H), 6.14 (s, 2H), 6.63-6.76 (m, 3H), 7.57 (s, 1H),8.06 (s, 1H), 9.13 (s, 1H), 9.23 (s, 1H), 11.78 (s, 1H). 457

441      0.14 (DMSO-d₆) δ 1.19-1.41 (m, 2H), 1.61 (m, 1H), 1.80 (m, 1H),1.95 (m, 1H), 2.30 (m, 2H), 2.56 (s, 3H), 2.66-2.93 (m, 2H), 3.74-4.00(m, 2H), 6.14 (s, 2H), 6.17- 6.20 (m, 1H), 6.25 (d, 2.3 Hz, 1H), 6.89(d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 8.07 (s, 1H), 9.51 (s, 1H), 9.67 (s,1H), 11.79 (s, 1H). 458

441      0.16 (Methanol-d₄) δ 1.18- 1.41 (m, 2H), 1.54-1.60 (m, 1H),1.74 (m, 1H), 2.15 (m, 1H), 2.33 (m, 2H), 2.57 (s, 3H), 2.89- 2.94 (m,2H), 4.37 (m, 2H), 6.06 (s, 2H), 6.54- 6.67 (m, 3H), 7.46 (s, 1H), 8.11(br.s, 1H). 459

400      0.095 (DMSO-d₆) δ 1.19 (m, 2H), 1.74 (t, J = 17.1 Hz, 2H), 2.06(m, 1H), 2.32 (d, J = 7.0 Hz, 2H), 2.55 (s, 3H), 2.77 (t, J = 12.6 Hz,1H), 3.13 (t, J = 12.7 Hz, 1H), 4.45 (m, 2H), 6.12 (s, 2H), 7.56 (s,1H), 8.02 (br, 0.5H), 8.10 (s, 1H), 8.46 (br, 0.5H), 11.80 (s, 1H). 460

400      0.3 (DMSO-d₆) δ 1.20 (m, 2H), 1.75 (dd, J = 35.5, 13.2 Hz, 2H),2.09 (m, 2H), 2.34 (d, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.75- 2.91 (m,2H), 3.11 (t, J = 12.7 Hz, 1H), 4.46 (d, J = 13.2 Hz, 1H), 6.13 (s, 2H),7.58 (s, 1H), 8.11 (s, 1H), 8.43 (s, 1H), 11.80 (s, 1H). 461

399      0.15 (DMSO-d₆) δ 1.06- 1.28 (m, 2H), 1.72 (m, 2H), 1.99-2.17(m, 1H), 2.33 (d, J = 6.9 Hz, 2H), 2.57 (s, 3H), 2.73 (m, 1H), 3.08 (t,J = 12.5 Hz, 1H), 4.54 (dd, J = 56.7, 13.3 Hz, 2H), 6.13 (s, 2H), 6.52(s, 1H), 7.58 (s, 1H), 7.79 (s, 1H), 8.11 (s, 1H), 11.81 (s, 1H), 13.12(s, 1H). 462

399      0.03 (DMSO-d₆) δ 1.22 (m, 2H), 1.75 (m, 2H), 2.09 (m, 1H), 2.33(d, J = 7.0 Hz, 2H), 2.57 (s, 3H), 2.78 (t, J = 12.6 Hz, 1H), 3.16 (t, J= 12.6 Hz, 1H), 4.48 (d, J = 13.0 Hz, 1H), 5.64 (d, J = 13.4 Hz, 1H),6.14 (s, 2H), 7.05 (t, J = 1.3 Hz, 1H), 7.22 (dd, J = 2.4, 1.1 Hz, 1H),7.58 (s, 1H), 8.12 (s, 1H), 11.81 (s, 1H), 12.84 (s, 1H). 463

413      0.4 (DMSO-d₆) δ 1.19 (m, 2H), 1.75 (d, J = 12.7 Hz, 2H), 2.1(m, 1H), 2.34 (m, 2H), 2.41 (s, 3H), 2.57 (d, J = 1.2 Hz, 3H), 2.84-2.89 (m, 1H), 4.28 (m, 1H), 4.47 (m, 2H), 6.14 (d, J = 1.1 Hz, 2H), 7.59(s, 1H), 7.70 (s, 1H), 8.12 (d, J = 3.7 Hz, 1H), 11.82 (s, 1H). 464

413      0.2 (DMSO-d₆) δ 1.16 (m, 2H), 1.71 (dd, J = 41.1, 13.1 Hz, 2H),2.03 (m, 4H), 2.29-2.36 (m, 2H), 2.57 (s, 3H), 2.73 (t, J = 12.4 Hz,1H), 3.02 (t, J = 12.8 Hz, 1H), 4.17 (m, 1H), 4.47 (d, J = 13.0 Hz, 1H),6.13 (s, 2H), 7.56 (s, 1H), 7.58 (s, 1H), 8.11 (s, 1H), 11.80 (s, 1H),12.77 (s, 1H). 465

413      0.046 (DMSO-d₆) δ 1.08-1.28 (m, 2H), 1.69-1.81 (m, 2H),2.01-2.13 (m, 1H), 2.13 (s, 1.5H), 2.17 (s, 1.5H), 2.32 (d, J = 6.9 Hz,2H), 2.57 (s, 3H), 2.75 (t, J = 12.4 Hz, 1H), 3.07-3.19 (m, 1H), 4.46(d, J = 13.0 Hz, 1H), 5.68 (d, J = 13.3 Hz, 1H), 6.14 (s, 2H), 6.74 (s,0.5H), 6.92 (s, 0.5H), 7.58 (s, 1H), 8.12 (s, 1H), 11.81 (s, 1H), 12.52(s, 0.5H), 12.60 (s, 0.5H). 466

414      0.7 (DMSO-d₆) δ 1.10-1.30 (m, 2H), 1.74 (dd, J = 34.4, 13.0 Hz,2H), 2.11 (m, H), 2.27-2.37 (m, 2H), 2.44 (s, 3H), 2.57 (s, 3H), 2.82(m, 1H), 3.03-3.20 (m, 1H), 3.86 (d, J = 13.6 Hz, 1H), 4.43 (d, J = 13.1Hz, 1H), 6.13 (s, 2H), 6.41 (s, 1H), 7.58 (s, 1H), 7.73 (s, 1H), 11.8(br, 1H) 467

413      0.058 (DMSO-d₆) δ 1.11-1.25 (m, 2H), 1.69-1.79 (m, 2H),2.01-2.14 (m, 1H), 2.31 (s, 3H), 2.34 (d, J = 7.0 Hz, 2H), 2.57 (d, J =1.2 Hz, 3H), 2.95 (br s, 2H), 4.31 (d, J = 13.3 Hz, 2H), 6.14 (d, J =1.2 Hz, 2H), 6.19-6.21 (m, 1H), 6.82 (dd, J = 3.2, 0.9 Hz, 1H), 7.58 (d,J = 1.2 Hz, 1H), 8.12 (d, J = 1.2 Hz, 1H), 11.81 (s, 1H). 468

443      0.070 (DMSO-d₆) δ 1.13-1.29 (m, 2H), 1.75 (d, J = 13.0 Hz, 2H),2.01-2.14 (m, 1H), 2.34 (d, J = 7.1 Hz, 2H), 2.56 (d, J = 0.9 Hz, 3H),2.98 (br s, 2H), 3.26 (d, J = 1.0 Hz, 3H), 4.20-4.34 (m, 2H), 4.38 (s,2H), 6.13 (d, J = 0.9 Hz, 2H), 6.55 (dd, J = 3.4, 0.9 Hz, 1H), 6.88 (dd,J = 3.4, 0.9 Hz, 1H), 7.57 (d, J = 0.9 Hz, 1H), 8.11 (d, J = 0.9 Hz,1H), 11.81 (s, 1H). 469

377      0.5 470

421      0.7 471

403      0.3 (DMSO-d₆, rotamers) δ 1.03-1.26 (m, 3H), 1.69 (m, 2H),1.76-1.85 (m, 2H), 1.94-2.04 (m, 2H), 2.31 (d, J = 7.1 Hz, 2H), 2.57 (s,3H), 2.99 (q, J = 13.7 Hz, 1H), 3.28-3.33 (m, 1H), 3.69-3.80 (m, 2H),3.97 (d, J = 13.8 Hz, 1H), 4.30 (d, J = 13.1 Hz, 1H), 4.63 (dd, J = 7.5,5.8 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H), 8.10 (s, 0.5H), 8.11 (s, 0.5H),11.79 (s, 0.5H), 11.80 (s, 0.5H). 472

403      0.3 (DMSO-d₆, rotamers) δ 1.16-1.20 (m, 3H), 1.68 (m, 2H),1.78-1.84 (m, 2H), 1.95-2.04 (m, 2H), 2.31 (d, J = 7.1 Hz, 2H), 2.57 (s,3H), 2.94-3.04 (m, 1H), 3.33 (m, 1H), 3.70-3.78 (m, 2H), 3.97 (d, J =13.9 Hz, 1H), 4.30 (d, J = 13.1 Hz, 1H), 4.63 (dd, J = 7.5, 5.8 Hz, 1H),6.13 (s, 2H), 7.58 (s, 1H), 8.10 (s, 0.5H), 8.11 (s, 0.5H), 11.79 (s,0.5H), 11.80 (s, 0.5H). 473

416   >50 474

417      0.13 (DMSO-d₆) δ 2.12-2.22 (m, 1H), 2.30-2.48 (m, 3H),2.52-2.62 (m, 7H), 3.19 (d, J = 1.6 Hz, 2H), 3.63 (m, 4H), 5.52 (m, 1H),6.14 (s, 2H), 7.63 (s, 1H), 8.33 (s, 1H), 12.68 (s, 1H). 475

431      0.3 (DMSO-d₆) δ 0.89-1.24 (m, 2H), 1.35-1.53 (m, 1H), 1.67 (t,J = 12.8 Hz, 2H), 1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.28 (d, J = 7.1 Hz,2H), 2.37 (m, 1H), 2.50, (m, 2H), 2.56 (s, 3H), 2.62 (m, 1H), 2.90-3.03(m, 1H), 3.56 (m, 1H), 3.72 (m, 1H), 3.87 (d, J = 13.6 Hz, 1H), 4.07 (m,1H), 4.21-4.41 (m, 4H), 7.54 (s, 1H), 8.04 (s, 1H), 11.43 (s, 1H). 476

417      0.3 (DMSO-d₆) δ 0.93-1.24 (m, 2H), 1.36-1.54 (m, 1H), 1.69 (m,2H), 1.73- 1.90 (m, 2H), 1.90-2.05 (m, 2H), 2.30 (d, J = 7.0 Hz, 2H),2.32-2.44 (m, 1H), 2.57 (s, 3H), 2.62 (m, 2H), 2.97 (t, J = 13.1 Hz,1H), 3.56 (m, 1H), 3.72 (m, 1H), 3.87 (d, J = 13.8 Hz, 1H), 4.07 (m,1H), 4.35 (d, J = 13.1 Hz, 1H), 6.13 (s, 2H), 6.57 (s, 1H), 7.58 (s,1H), 11.80 (s, 1H). 477

417      0.4 (DMSO-d₆) δ 0.93-1.24 (m, 3H), 1.47 (m, 1H), 1.68 (t, J =14.1 Hz, 2H), 1.92-2.07 (m, 2H), 2.31 (d, J = 7.1 Hz, 2H), 2.33- 2.48(m, 3H), 2.57 (s, 3H), 2.98 (dd, J = 13.6, 11.2 Hz, 1H), 3.15-3.26 (m,1H), 3.60 (m, 1H), 3.69 (m, 1H), 3.77-3.88 (m, 2H), 4.35 (d, J = 13.1Hz, 1H), 6.14 (s, 2H), 7.58 (s, 1H), 8.11 (s, 1H), 11.81 (s, 1H). 478

431   >10 479

416   >10 480

363      1.4 (DMSO-d₆) δ 1.17-1.48 (m, 2H), 1.54-1.69 (m, 1H), 1.75-1.96(m, 2H), 1.97 (s, 1.5H), 1.98 (s, 1.5H), 2.18-2.48 (m, 2.5H), 2.65-2.76(m, 0.5H), 2.83-2.92 (m, 0.5H), 2.96-3.05 (m, 0.5H), 3.62-3.77 (m, 1H),3.82 (s, 3H), 4.02- 4.09 (m, 0.5H), 4.18- 4.25 (m, 0.5H), 6.12 (s, 2H),7.37 (s, 0.5H), 7.38 (s, 0.5H), 7.93 (s, 0.5H), 7.98 (s, 0.5H), 10.79(s, 0.5H), 10.82 (s, 0.5H). 481

419      2.2 (DMSO-d₆) δ 1.20-1.47 (m, 2H), 1.56-1.71 (m, 1H), 1.71-2.06(m, 6.5H), 2.21-2.44 (m, 2H), 2.51-2.58 (m, 0.5H), 2.65-2.73 (m, 0.5H),2.83-2.91 (m, 0.5H), 2.95-3.10 (m, 0.5H), 3.59-3.79 (m, 2H), 3.82 (s,3H), 3.85- 3.95 (m, 0.5H), 4.04- 4.12 (m, 0.5H), 4.13- 4.20 (m, 0.5H),4.56- 4.69 (m, 1H), 6.12 (s, 2H), 7.38 (s, 1H), 7.95 (s, 0.5H), 7.98 (s,0.5H), 10.76-10.85 (m, 1H). 482

419      1.4 (DMSO-d₆) δ 0.99-1.23 (m, 2H), 1.65-1.74 (m, 2H), 1.74-1.90(m, 2H), 1.90-2.08 (m, 3H), 2.32 (d, J = 7.1 Hz, 2H), 2.52-2.61 (m, 1H),2.92- 3.05 (m, 1H), 3.68-3.78 (m, 2H), 3.82 (s, 3H), 3.97 (d, J = 13.7Hz, 1H), 4.31 (d, J = 13.1 Hz, 1H), 4.59-4.69 (m, 1H), 6.12 (s, 2H),7.38 (s, 1H), 7.99 (d, J = 3.6 Hz, 1H), 10.81 (d, J = 5.6 Hz, 1H). 483

469      0.64 (DMSO-d₆) δ 1.11-1.27 (m, 2H), 1.55-1.83 (m, 2H),1.97-2.10 (m, 1H), 2.33 (d, J = 7.0 Hz, 2H), 2.76 (br s, 1H), 3.02 (brs, 1H), 3.29 (s, 3H), 3.54 (br s, 1H), 3.81 (s, 3H), 4.42 (s, 2H), 4.43(br s, 1H), 6.10 (s, 2H), 7.31-7.39 (m, 5H), 7.97 (s, 1H), 10.82 (s,1H). 484

426      0.46 (DMSO-d₆) δ 1.13-1.30 (m, 2H), 1.63 (d, J = 13.1 Hz, 1H),1.80 (d, J = 13.1 Hz, 1H), 2.01- 2.15 (m, 1H), 2.35 (dd, J = 7.1, 2.5Hz, 2H), 2.77-2.88 (m, 1H), 3.01-3.11 (m, 1H), 3.41 (d, J = 13.5 Hz,1H), 3.82 (s, 3H), 4.45 (d, J = 13.1 Hz, 1H), 6.12 (s, 2H), 7.32-7.41(m, 3H), 7.99 (s, 1H), 8.62- 8.70 (m, 2H), 10.84 (s, 1H). 485

424      0.24 (DMSO-d₆) δ 0.92-1.35 (m, 2H), 1.68 (m, 2H), 1.94-2.14 (m,1H), 2.31 (m, 2H), 2.56 (s, 3H), 2.58-3.22 (m, 3H), 3.50 (d, J = 13.6Hz, 1H), 4.22-4.37 (m, 4H), 7.40-7.49 (m, 1H), 7.54 (s, 1H), 7.81 (m,1H), 8.04 (s, 1H), 8.54-8.69 (m, 2H), 11.45 (d, J = 8.2 Hz, 1H). 486

467      0.188 (DMSO-d₆) δ 1.20 (br s, 2H), 1.61 (br s, 1H), 1.75 (br s,1H), 1.97- 2.10 (m, 1H), 2.32 (d, J = 7.0 Hz, 2H), 2.56 (s, 3H), 2.77(br s, 1H), 3.03 (br s, 1H), 3.30 (s, 3H), 3.53 (br s, 1H), 4.23-4.29(m, 2H), 4.31-4.36 (m, 2H), 4.45 (br s, 1H), 4.44 (s, 2H), 7.25-7.31 (m,2H), 7.35-7.43 (m, 2H), 7.53 (s, 1H), 8.04 (s, 1H), 11.45 (s, 1H). 487

443      0.25 (DMSO-d₆) δ 0.89-1.27 (m, 2H), 1.73 (m, 2H), 1.97-2.18 (m,1H), 2.31 (m, 2H), 2.56 (s, 3H), 2.58-2.76 (m, 2H), 2.98 (m, 1H),4.23-4.39 (m, H), 4.42 (d, J = 5.8 Hz, 2H), 5.36 (t, J = 5.9 Hz, 1H),6.41 (dd, J = 3.4, 0.7 Hz, 1H), 6.86 (d, J = 3.3 Hz, 1H), 7.54 (s, 1H),8.04 (s, 1H), 11.44 (s, 1H). 488

473      0.015 (DMSO-d₆) δ 1.21 (m, 2H), 1.73 (d, J = 12.1 Hz, 2H), 2.07(m, 1H), 2.32 (d, J = 7.0 Hz, 2H), 2.56 (s, 3H), 2.98 (br, 2H).3.23-3.31 (m, 3H), 4.14-4.38 (m, 6H), 4.58 (d, J = 0.9 Hz, 2H), 7.02(dt, J = 3.6, 0.7 Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.54 (s, 1H), 8.05(s, 1H), 11.45 (s, 1H). 489

457      0.15 (DMSO-d₆) δ 1.20 (m, 2H), 1.75 (m, 2H), 2.07 (m, 1H), 2.32(d, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.99 (br, 2H). 3.26 (s, 2H),4.17-4.37 (m, 6H), 4.38 (s, 3H), 6.55 (d, J = 3.4 Hz, 1H), 6.88 (d, J =3.4 Hz, 1H), 7.54 (s, 1H), 8.05 (s, 1H), 11.44 (s, 1H). 490

444      0.16 (DMSO-d₆) δ 1.18 (m, 2H), 1.66-1.87 (m, 2H), 2.06 (m, 1H),2.26-2.35 (m, 2H), 2.56 (s, 3H), 2.83 (m, 1H), 3.09 (m, 1H), 3.84 (d, J= 13.5 Hz, 1H), 4.22-4.38 (m, 4H), 4.43 (d, J = 13.2 Hz, 1H), 4.60 (d, J= 5.2 Hz, 2H), 5.73 (t, J = 6.0 Hz, 1H), 6.55 (s, 1H), 7.54 (d, J = 0.7Hz, 1H), 7.96 (s, 1H). 8.04 (d, J = 1.0 Hz, 1H), 11.44 (s, 1H). 491

458      0.16 (DMSO-d₆) δ 1.20 (m, 2H), 1.74 (dd, J = 34.5, 12.9 Hz,2H), 2.10 (m, 1H), 2.32 (dd, J = 7.1, 1.8 Hz, 2H), 2.56 (s, 3H),2.77-2.90 (m, 1H), 3.13 (t, J = 12.4 Hz, 1H), 3.32 (s, 3H), 3.83 (d, J =13.6 Hz, 1H), 4.23-4.37 (m, 4H), 4.44 (d, J = 13.3 Hz, 1H), 4.59 (s,2H), 6.71 (s, 1H), 7.54 (s, 1H), 8.04 (s, 1H), 11.44 (s, 1H). 492

361      0.17 (DMSO-d₆) δ 1.09-1.24 (m, 2H), 1.67 (t, J = 15.0 Hz, 2H),1.97 (m, 4H), 2.28 (d, J = 7.1 Hz, 2H), 2.5 (m, 2H), 2.56 (s, 3H), 3.00(m, 1H), 3.77 (d, J = 13.7 Hz, 1H), 4.22-4.37 (m, 4H), 7.54 (s, 1H),8.05 (s, 1H), 11.44 (s, 1H). 493

417      0.45 (DMSO-d₆, rotamers) δ 0.89-1.26 (m, 3H), 1.68 (m, 2H),1.81 (q, J = 7.4 Hz, 2H), 1.97 (m, 2H), 2.29 (d, J = 7.1 Hz, 2H), 2.56(s, 3H), 2.99 (q, J = 13.7 Hz, 1H), 3.30 (m, 2H), 3.74 (dq, J = 13.1,6.9, 6.3 Hz, 2H), 3.99 (d, J = 16.4 Hz, 1H), 4.21-4.40 (m, 4H), 4.63(dd, J = 7.3, 5.9 Hz, 1H), 7.54 (s, 1H), 8.04 (s, 0.5H), 8.05 (s, 0.5H),11.43 (s, 0.5H), 11.44 (s, 0.5H). 494

417      0.3 (DMSO-d₆, rotamers) δ 1.02-1.26 (m, 3H), 1.68 (m, 2H), 1.81(q, J = 7.4 Hz, 2H), 1.97 (m, 2H), 2.29 (d, J = 7.1 Hz, 2H), 2.56 (s,3H), 2.99 (q, J = 13.7 Hz, 1H), 3.30 (m, 2H), 3.74 (dq, J = 13.1, 6.9,6.3 Hz, 2H), 3.99 (d, J = 16.4 Hz, 1H), 4.21-4.40 (m, 4H), 4.63 (dd, J =7.3, 5.9 Hz, 1H), 7.54 (s, 1H), 8.04 (s, 0.5H), 8.05 (s, 0.5H), 11.43(s, 0.5H), 11.44 (s, 0.5H). 495

417      0.2 (DMSO-d₆, rotamers) δ 1.04-1.23 (m, 3H), 1.68 (m, 2H), 1.81(m, 2H), 1.99 (m, 2H), 2.28 (d, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.99 (q,J = 13.8, 13.4 Hz, 1H), 3.33 (m, 2H), 3.74 (dt, J = 13.7, 7.2 Hz, 2H),3.96 (d, J = 13.9 Hz, 1H), 4.19-4.39 (m, 4H), 4.63 (dd, J = 7.2, 6.0 Hz,1H), 7.54 (s, 1H), 8.03 (s, 0.5H), 8.04 (s, 0.5H), 11.42 (s, 0.5H),11.43 (s, 0.5H). 496

335   >10 497

391   >10 498

401   >10 499

401   >10 500

401      4 501

398   >50 502

410      0.170 503

453      0.099 504

413      0.159 505

399      0.130 506

410      0.113 507

410      0.275 508

377      1.2 (DMSO-d₆) δ 1.15-1.44 (m, 2H), 1.54-1.68 (m, 1H), 1.72-1.93(m, 2H), 1.95 (s, 1.5H), 1.96 (s, 1.5H), 2.16-2.46 (m, 2.5H), 2.63-2.76(m, 0.5H), 2.82-2.89 (m, 0.5H), 2.94-3.02 (m, 0.5H), 3.60-3.76 (m, 1H),3.80 (s, 3H), 3.98-4.07 (m, 0.5H), 4.16-4.22 (m, 0.5H), 4.21-4.26 (m,2H), 4.27-4.34 (m, 2H), 7.36 (s, 0.5H), 7.36 (s, 0.5H), 7.85 (s, 0.5H),7.90 (s, 0.5H), 10.51 (s, 0.5H), 10.53 (s, 0.5H). 509

349      0.18 (DMSO-d₆, rotamers) δ 2.01 (s, 3H), 2.57 (s, 3H),2.93-2.99 (m, 1H), 3.11-3.17 (m, 1H), 3.43-3.50 (m, 1H), 3.65-3.84 (m,4H), 4.14 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 12.8 Hz, 1H), 6.13 (s, 1H),6.14 (s, 1H), 7.58 (s, 0.5H), 7.59 (s, 0.5H), 8.11 (s, 0.5H), 8.12 (s,0.5H), 11.85 (s, 0.5H), 11.87 (s, 0.5H). 510

405      0.15 (DMSO-d₆, rotamers) δ 1.12 (d, J = 6.6 Hz, 1H), 1.27 (d, J= 7.1 Hz, 1H), 1.80-1.83 (m, 1H), 2.03- 2.08 (m, 1H), 2.57 (s, 3H),2.64-2.69 (m, 1H), 2.95-2.99 (m, 1H), 3.12- 3.15 (m, 1H), 3.42-3.48 (m,1H), 3.72-3.85 (m, 5H), 4.12 (d, J = 13.2 Hz, 1H), 4.26 (d, J = 13.1 Hz,1H), 4.67 (m, 1H), 6.13 (s, 1H), 6.14 (s, 1H), 7.58 (s, 1H), 8.10 (s,0.5H), 8.12 (s, 0.5H), 11.83 (s, 0.5H), 11.86 (s, 0.5H). 511

377 >>10 512

387      7.7 513

397      2.7 (DMSO-d₆) δ 1.23-1.28 (m, 1H), 1.44 (m, 1H), 1.59 (m, 1H),1.71 (m, 1H), 1.95 (m, 1H), 2.13- 2.25 (m, 2H), 2.79-2.99 (m, 2H),3.71-3.75 (br.s, 3H), 4.22 (m, 1H), 4.33 (m, 1H), 5.95 (s, 2H), 6.83(br.s, 1H), 7.13 (br.s, 1H), 7.35-7.42 (m, 5H), 9.09 (br.s, 1H). 514

403      1.0 (DMSO-d₆) δ 1.23-1.30 (m, 1H), 1.44-1.48 (m, 1H), 1.70-1.73(m, 1H), 1.83-1.86 (m, 1H), 1.96 (m, 1H), 2.30 (m, 2H), 2.81-2.99 (m,2H), 3.73 (s, 3H), 4.20-4.23 (m, 2H), 5.95 (s, 2H), 6.84 (s, 1H), 7.06(t, J = 4.0 Hz, 1H), 7.35 (s, 1H), 7.38 (dd, J = 3.6, 1.1 Hz, 1H), 7.72(dd, J = 5.0, 1.1 Hz, 1H), 9.08 (s, 1H). 515

385      0.5 (DMSO-d₆) δ 1.08-1.13 (m, 1H), 1.20 (t, J = 7.4 Hz, 3H),1.46 (m, 1H), 1.73 (t, J = 16.6 Hz, 2H), 1.94 (m, 1H), 2.29 (d, J = 7.0Hz, 2H), 2.56 (m, 1H), 2.78 (td, J = 11.4, 2.5 Hz, 1H), 3.01 (q, J = 7.3Hz, 2H), 3.46 (m, 1H), 3.57 (dd, J = 11.7, 3.8 Hz, 1H), 3.75 (s, 3H),5.94 (s, 2H), 6.84 (s, 1H), 7.39 (s, 1H), 9.06 (s, 1H).

EXAMPLE 33 Synthesis ofN-(6-Acetylbenzo[d][1,3]dioxol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(270)

Prepared in a similar manner as in Example 24b from2-(tetrahydro-2H-pyran-4-yl)acetic acid (70 mg, 0.5 mmol),1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one (90 mg, 0.5 mmol), andTEA (150 mg, 1.5 mmol) to give 87 mg (58% yield) of the title compoundas a light yellow solid. Alternatively, prepared as in Example 1c from1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one and2-(tetrahydro-2H-pyran-4-yl)acetyl chloride. MS 306 (M+H+).

Compounds in Table 9 were prepared in similar manner as in Example 1cand/or 24b from 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethan-1-one and thecorresponding commercially available carboxylic acids and/or acylchlorides.

TABLE 9 Obs Mol Ion; MS hT2R54 SID Structure (M + 1) IC50 (uM) ¹H NMR(400 MHz) 270

306 0.561 (CD3OD) δ 1.71-1.84 (m, 2H), 2.07-2.15 (m, 2H), 2.51-2.61 (m,1H), 2.78 (d, J = 7.2 Hz, 2H), 3.07 (s, 3H), 3.27 (d, J = 0.5 Hz, 1H),3.80 (td, J = 11.9, 2.2 Hz, 2H), 4.27-4.36 (m, 2H), 6.53-6.60 (m, 2H),7.96 (s, 1H), 8.83 (s, 1H), 12.58 (s, 1H). 271

306 0.152 (DMSO-d₆) δ 1.19-1.31 (m, 1H), 1.37-1.56 (m, 3H), 1.61 (br d,J = 13.1 Hz, 1H), 1.70-1.82 (m, 1H), 2.38 (dd, J = 14.8, 8.8 Hz, 1H),2.47-2.53 (m, 1H), 2.56 (s, 3H), 3.33-3.41 (m, 1H), 3.66-3.73 (m, 1H),3.79-3.97 (m, 1H), 6.13 (br d, J = 1.0 Hz, 2H), 7.58 (s, 1H), 8.15 (s,1H), 11.85 (s, 1H). 272

292 1.39 (DMSO-d₆) δ 1.49-1.59 (m, 1H), 1.98-2.08 (m, 1H), 2.45-2.50 (m,3H), 2.53-2.60 (m, 4H), 3.27- 3.32 (m, 1H), 3.58-3.65 (m, 1H), 3.68-3.75(m, 1H), 3.82 (dd, J = 8.4, 6.8 Hz, 1H), 6.13 (s, 2H), 7.58 (s, 1H),8.08 (s, 1H), 11.80 (s, 1H). 273

299 0.454 (DMSO-d₆) δ 2.53 (d, J = 0.8 Hz, 3H), 3.81 (s, 2H), 6.13 (d, J= 0.8 Hz, 2H), 7.29-7.43 (m, 1H), 7.57 (d, J = 0.7 Hz, 1H), 7.73-7.77(m, 1H), 8.07 (d, J = 0.8 Hz, 1H), 8.47-8.51 (m, 1H), 8.54 (d, J = 2.3Hz, 1H), 11.83 (s, 1H). 274

314 0.554 (DMSO-d₆) δ 2.51 (s, 3H), 3.57 (s, 2H), 6.12 (s, 2H), 6.72 (d,J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.55 (s, 1H), 8.14 (s, 1H),9.34 (s, 1H), 11.80 (s, 1H). 275

304 0.704 (DMSO-d₆) δ 2.52 (s, 3H), 3.75 (s, 2H), 6.13 (s, 2H), 7.08(dd, J = 4.9, 1.3 Hz, 1H), 7.34-7.44 (m, 1H), 7.52 (dd, J = 4.9, 2.9 Hz,1H), 7.56 (s, 1H), 8.13 (s, 1H), 11.81 (s, 1H). 276

328 0.804 (DMSO-d₆) δ 2.50 (s, 3H), 3.64 (s, 2H), 3.76 (s, 3H), 6.12 (s,2H), 6.94 (td, J = 7.4, 1.1 Hz, 1H), 7.01 (dd, J = 8.2, 1.0 Hz, 1H),7.24- 7.34 (m, 2H), 7.55 (s, 1H), 8.16 (s, 1H), 11.76 (s, 1H). 277

312 0.74 (DMSO-d₆) δ 2.26 (s, 3H), 2.50 (s, 3H), 3.75 (s, 2H), 6.12 (d,J = 0.6 Hz, 2H), 7.16-7.22 (m, 3H), 7.26- 7.30 (m, 1H), 7.55 (d, J = 0.6Hz, 1H), 8.15 (d, J = 0.6 Hz, 1H), 11.79 (s, 1H). 278

312 1.224 (DMSO-d₆) δ 2.54 (s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 2.92 (t, J= 1.6 Hz, 2H), 6.13 (s, 2H), 7.14-7.31 (m, 4H), 7.56 (s, 1H), 8.09 (s,1H), 11.81 (s, 1H). 279

358 1.472 (DMSO-d₆) δ 2.51 (s, 3H), 3.62 (s, 2H), 3.71 (d, J = 4.5 Hz,6H), 6.12 (s, 2H), 6.77- 7.03 (m, 3H), 7.55 (s, 1H), 8.16 (s, 1H), 11.75(s, 1H). 280

330 1.72 (DMSO-d₆) δ 2.04 (s, 3H), 2.17 (d, J = 0.6 Hz, 3H), 2.50 (d, J= 0.6 Hz, 2H), 3.41 (s, 2H), 3.64 (s, 3H), 6.12 (d, J = 0.6 Hz, 2H),7.55 (d, J = 0.5 Hz, 1H), 8.19 (d, J = 0.6 Hz, 1H), 11.71 (s, 1H). 281

328 1.805 (DMSO-d₆) δ 2.52 (s, 3H), 3.69 (s, 2H), 3.75 (s, 3H), 6.13 (s,2H), 6.82-6.95 (m, 3H), 7.22-7.29 (m, 1H), 7.56 (s, 1H), 8.11 (s, 1H),11.83 (s, 1H). 516

264 3 517

290 0.414 (DMSO-d₆) δ 1.11-1.24 (m, 2H), 1.45-1.67 (m, 4H), 1.71-1.82(m, 2H), 2.15- 2.27 (m, 1H), 2.35 (d, J = 7.4 Hz, 2H), 2.57 (s, 3H),6.13 (s, 2H), 7.58 (s, 1H), 8.14 (s, 1H), 11.85 (s, 1H). 518

317 3.8 519

405 0.9 (DMSO-d₆) δ 1.23 (m, 2H), 1.35 (s, 9H), 1.56-1.62 (m, 1H),1.73-1.79 (m, 1H), 1.88 (br.s, 1H), 2.29 (d, J = 7.5 Hz, 2H), 2.57 (s,3H), 2.84 (br.s, 2H), 3.77 (br.s, 2H), 6.14 (s, 2H), 7.59 (s, 1H), 8.12(s, 1H), 11.83 (s, 1H). 520

278 0.308 (DMSO-d₆) δ 1.11-1.23 (m, 2H), 1.43-1.64 (m, 4H), 1.67- 1.78(m, 2H), 2.11-2.24 (m, 1H), 2.32 (d, J = 7.4 Hz, 2H), 3.74 (d, J =1.2Hz, 3H), 5.94 (d, J = 1.2 Hz, 2H), 6.84 (d, J = 1.1 Hz, 1H), 7.42 (d,J = 1.1 Hz, 1H), 8.92 (s, 1H). 521

294 2.256 (DMSO-d₆) δ 1.17-1.30 (m, 1H), 1.39-1.53 (m, 3H), 1.56-1.64(m, 1H), 1.72- 1.81 (m, 1H), 2.32-2.40 (m, 1H), 2.51-2.57 (m, 1H),3.34-3.42 (m, 1H), 3.61- 3.69 (m, 1H), 3.76 (d, J = 1.2 Hz, 3H),3.86-3.93 (m, 1H), 5.92-5.96 (m, 2H), 6.86 (d, J = 1.1 Hz, 1H), 7.60 (d,J = 1.1 Hz, 1H), 9.16 (s, 1H). 522

316 0.886 (DMSO-d₆) δ 3.63 (s, 2H), 3.76 (d, J = 1.1 Hz, 3H), 3.82 (d, J= 1.1 Hz, 3H), 5.93 (d, J = 1.1 Hz, 2H), 6.86 (d, J = 1.1 Hz, 1H),6.88-6.95 (m, 1H), 7.02 (d, J = 8.1 Hz, 1H), 7.19-7.29 (m, 2H), 7.58 (d,J = 1.1 Hz, 1H), 8.88 (s, 1H). 523

288 2.307 (DMSO-d₆) δ 2.53 (s, 3H), 3.82 (s, 2H), 6.14 (s, 2H),6.37-6.39 (m, 1H), 6.45 (dd, J = 3.2, 1.9 Hz, 1H), 7.57 (s, 1H), 7.61(dd, J = 1.9, 0.9 Hz, 1H), 8.12 (s, 1H), 11.86 (s, 1H). 524

292 0.868 (DMSO-d₆) δ 3.70 (s, 2H), 3.75 (d, J = 1.1 Hz, 3H), 5.94 (d, J= 1.1 Hz, 2H), 6.86 (d, J = 1.1 Hz, 1H), 7.08 (dt, J = 4.9, 1.3 Hz, 1H),7.28-7.36 (m, 1H), 7.42-7.53 (m, 2H), 9.13 (s, 1H). 525

407 3.0 (DMSO-d₆) δ 1.03 (d, J = 6.7 Hz, 3H), 1.38 (s, 9H), 1.53- 1.72(m, 5H), 2.37-2.42 (m, 1H), 3.74 (s, 3H), 3.93 (m, 4H), 5.94 (s, 2H),6.84 (s, 1H), 7.39 (s, 1H), 8.93 (s, 1H). 526

242 (DMSO-d₆) δ 1.07 (t, J = 7.5 Hz, 3H), 2.45 (q, J = 7.5 Hz, 2H), 4.25(s, 2H), 5.99 (s, 2H), 6.82 (s, 1H), 6.83 (s, 1H), 9.55 (s, 1H), MS 242(MH⁺). 527

272 (DMSO-d₆) δ 3.85 (s, 3H), 4.44 (s, 2H), 6.15 (s, 2H), 7.42 (s, 1H),8.05 (s, 1H), 11.57 (s, 1H). 528

421 ~1 (DMSO-d₆) δ 1.10-1.35 (m, 3H), 1.33 (s, 9H), 1.56 (m, 1H), 1.75(m, 1H), 1.86 (m, 1H), 2.29 (m, 2H), 2.82 (m, 1H), 3.62-3.79 (m, 2H),3.82 (s, 3H), 6.11 (s, 2H), 7.36 (s, 1H), 7.98 (s, 1H), 10.83 (s, 1H).529

336 12 530

286 (DMSO-d₆) δ 3.84 (s, 3H), 4.24-4.29 (m, 2H), 4.31- 4.37 (m, 2H),4.42 (s, 2H), 7.44 (s, 1H), 8.01 (s, 1H), 11.33 (s, 1H). 531

282 (DMSO-d₆) δ 1.68-1.79 (m, 4H), 2.66-2.79 (m, 4H), 3.86 (s, 3H), 4.42(s, 2H), 7.70 (s, 1H), 8.14 (s, 1H), 11.23 (s, 1H).

EXAMPLE 34 Synthesis of1-(6-Methyl-2-phenylpyrimidin-4-yl)piperidine-4-carboxamide (A)

A mixture of 4-chloro-6-methyl-2-phenylpyrimidine (1 g, 4.89 mmol) andpiperidine-4-carboxamide (0.627 g, 4.89 mmol) and trimethylamine (1.02mL, 7.34 mmol) in anhydrous DMF (25 mL) was heated to reflux for 4hours, upon completion, the reaction mixture was cooled to roomtemperature, and then was concentrated to dry, the residue was stirredin a mixed solution of EtOAc (10 mL) and water (20 mL) for about 30 min.and then the solid product was collected by filtration to obtain 1.4 gcompound, then it was re-crystallized from EtOH/H₂O, after dry obtained900 mg of the title compound as a white solid in 62% yield. MS (MH⁺)297.

Other T2R54 bitter blockers provided by the present disclosure orsuitable to be used for methods of the present disclosure include thefollowing compounds.

Obs Mol Cmpd Ion; MS hT2R54 No. Compound (M + 1) IC₅₀ (μM) ¹H NMR (400MHz) A

297 2.9 (400 MHz) δ: 1.48 (m, 2H), 1.78 (m, 2H), 2.32 (s, 3H), 2.40 (m,1H), 2.94 (m, 2H), 4.49 (m, 2H), 6.7 (s, 1H), 6.79 (s, 1H), 7.29 (s,1H), 7.44 (m, 3H), 8.31 (m, 1H); B

340 1.8

Compounds described in this application show potent bitter antagonisteffect on T2R54 in receptor based assays. In some cases they alsoexhibit bitter antagonist effect on other T2Rs. For example, in additionto T2R54, Cmpd 1 (Table 2) exhibits significant bitter blocking effecton T2R⁶¹, T2R⁶⁴, and T2R⁷⁵, respectively. Antagonist activity of1-(6-methyl-2-phenylpyrimidin-4-yl)piperidine-4-carboxamide against apanel of bitter taste receptors is shown in Table 10, with the identityof each T2R as indicated in the left column, and the percentage activityremaining is indicated in the far right column.

TABLE 10 ΔF/F Compound 1 R1 0.29 91 R3 0.20 83 R4 0.08 112 R5 0.31 104R7 0.30 97 R8 0.48 108 R9 0.27 80 R10 0.51 82 R13 0.25 90 R14 0.44 91R16 1.13 100 R44 0.15 89 R51 0.49 103 R54 0.20 15 R55 0.15 100 R61 0.4861 R63 0.22 83 R63Rs 0.48 107 R64 0.14 42 R65 0.34 87 R67 0.78 90 R710.17 97 R75 0.27 5

The results shown in Table 10 demonstrate that in this assay, in thepresence of Compound 1 and a bitter compound only 61% of activity ofT2R⁶¹ was retained, only 42% of the activity of T2R⁶⁴ was retained, only15% of the activity of T2R54 was retained, and only 5% of the activityof T2R⁷⁵ was retained, as compared to the activity of the receptor inthe presence of the bitter compound alone.

EXAMPLE 35 Sensory Experiments

To determine the effectiveness of an individual antagonist in blockingthe bitterness, taste tests were performed comparing epigallocatechingallate (EGCg) alone, which is known to activate T2R54 with EGCg and abitter blocker described herein, namely compound 22 (Table 2). Theresults shown in Table 11 below indicate clearly that compound 22 hasthe ability to reduce EGCg bitterness.

TABLE 11 Samples Total 600 uM EGCG 36 600 uM EGCG + 15 uM of compound 2220 Total 56 600 uM EGCG alone selected as more bitter (p-value) 0.044

EXAMPLE 36 Method of Preparing the Composition

In order to manipulate or block bitter taste associated with any of theapplications discussed herein, the compounds and compositions discussedherein may be used in combination with any of the products necessary forany of said applications. For example, the compounds and compositions ofthe present disclosure may be combined with any element associated witha product and/or application discussed herein using a method recognizedin the art for preparing such a composition.

In order to manipulate or block bitter taste associated with any of theapplications discussed herein, the compounds and compositions discussedherein may be used in combination with any of the products necessary forany of said applications, and may further be combined with one or moreof the excipients and other additive compounds discussed in detailherein. For example, the compounds and compositions of the presentdisclosure may be combined with one or more of such compounds using anart recognized method, and then this mixture may further be combinedwith any element associated with a product and/or application discussedherein using a method recognized in the art for preparing such acomposition.

The composition may be prepared e.g., by combining the ingredients withany of the compounds as shown in the table below:

TABLE 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Compound(s) ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Cooling agent(s) ⋄ ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● Pharmaceutical ingredient(s) ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄⋄ Food additive(s) ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Flavorant(s) ⋄ ⋄⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Bitter compounds ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Foodstuffs ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ Compounds known to be used in ⋄ ⋄ ●● ● ● ● ● oral care products, and/or consumer products, and/or animalproducts, and/or pet care products Plant products, cannabis-derived, ⋄ ⋄● ⋄ ⋄ ⋄ ⋄ ● ● or cannabis-related products Preparations ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄Beverages, and/or scents, and/or ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ perfumes, and/or odorantsSilicone compound(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ Abrasive(s) ⋄ ⋄⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● Surfactant(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄● ⋄ ⋄ ⋄ ⋄ Warming agent(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ Probioticbacteria or supplement(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ 19 20 2122 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Compound(s) ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● Cooling agent(s) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●Pharmaceutical ingredient(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Foodadditive(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Flavorant(s) ⋄ ⋄ ⋄ ⋄ ⋄ ⋄⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ Bitter compounds ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄⋄ ⋄ Foodstuffs ● ● ● ● ● Compounds known to be used in oral careproducts, and/or consumer products, and/or animal products, and/or petcare products Plant products, cannabis-derived, ● ● ● orcannabis-related products Preparations ● ● ● ● ● Beverages, and/orscents, and/or ● ● ● ● ● perfumes, and/or odorants Silicone compound(s)⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ Abrasive(s) ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄⋄ ⋄ ● ⋄ ⋄ ⋄ Surfactant(s) ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ Warmingagent(s) ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ⋄ Probiotic bacteria orsupplement(s) ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ● ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ⋄ ● ● refers to aningredient that is typically be present in a composition ⋄ refers to aningredient that could be present in a composition

Preparations refer to any combination of pharmaceutical preparations andtopical preparations. Pharmaceutical ingredient(s) refer to anycombination of inactive drug ingredients and active pharmaceuticalingredients. Flavorant(s) refer to any combination of sweetener(s), sourflavorant(s), umami flavorant(s), salty flavorant(s), bitterant(s), andflavor enhancer(s). Compound(s) refers to one or a combination of two ormore compounds of the present invention, as described above.

EXAMPLE 37 Cell-Based Assay for Measuring hT2R54 Inhibition

Cells stably expressing hT2R54 and a promiscuous G protein were seededin 384 well plates 24 hours prior to the experiment. Cells were loadedwith the calcium indicator Fluo4AM, washed and loaded in a FLIPRinstrument with a compound plate containing increasing doses ofacetaminophen in quadruplicates and prepared at 2× of finalconcentration. Baseline was recorded for 10 seconds, then 25 μl of Cmpd109 (Table 4) was added onto 25 μl of cells and resulting changes influorescence were monitored over an additional 3 minutes. The host cellline overexpressing the G protein but not hT2R54 was treated asdescribed above. Results of this experiment are shown in FIG. 1 . Theresults show that cells expressing hT2R54, but not control cells,exhibited a measurable change in intracellular calcium in response tothe bitter tastant acetaminophen.

The ability of a test compound that blocks bitter taste elicited throughhT2R54 was measured in this assay, as follows. Cells stably expressinghT2R54 and a promiscuous G protein were seeded in 384 well plates 24hours prior to the experiment.

Cells were loaded with the calcium indicator Fluo4AM, washed and loadedin a FLIPR instrument with a compound plate containing increasing dosesof acetaminophen in buffer and increasing doses of acetaminophen withdepicted fixed concentrations of Cmpd 109 (Table 4). Base line wasrecorded for 10 seconds, then 25 μl of compound and compound mixtureswere added onto 25 μl of cells and resulting changes in fluorescencewere monitored over an additional 3 minutes. Results of this experimentare shown in FIG. 2 . The concentration of test compound that blockshalf of the response when the bitter compound alone is present ispresented as the EC₅₀ or IC₅₀ value.

In the examples above, the EC₅₀ of compounds for blocking bitter tasteelicited through T2R54 was measured in the same manner.

What is claimed is:
 1. A compound of formula (I)

or a salt thereof, wherein: X¹ and X² are each an oxygen atom; X³ is adirect bond or >CH₂; X⁴ is >CH₂; R^(A) is a halogen atom, —CN, nitro,—OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂,—O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C(O)—(C₁₋₆alkyl),—O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),—C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),—O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆), —N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl),—S(O)₂—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,C₂₋₆haloalkenyloxy, or (C₁₋₆alkoxy)-C₁₋₆alkyl; R¹ is —C(O)—R^(1A);R^(1A) is C₁₋₆ alkyl, which is optionally substituted one or more timesby substituents selected independently from R^(1Y); R^(1Y) is a halogenatom, oxo, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H,—C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂,—S(O)₂—(C₁₋₆alkyl), —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),—S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, C₂₋₁₄ heteroaryl,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy,C₂₋₆haloalkenyloxy, or (C₁₋₆alkoxy)-C₁₋₆alkyl; R² is

X⁵ is >NR^(2G); X⁶ is C₁₋₆ alkylene, which is optionally substituted oneor more times by substituents selected independently from R^(1Y); X⁷ is>N—R^(2L); X⁸, X⁹, X¹⁰, and X¹¹ are each independently>C(R^(2M))(R^(2N)); R^(2M) and R^(2N) are each independently a hydrogenatom, a halogen atom, —CN, nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH,—NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—NH—C(O)—O—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl),—C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl), —O—S(O)₂—(C₁₋₆alkyl),—NH—S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl),—S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl,C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl,C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, C₂₋₆ haloalkenyloxy, or(C₁₋₆alkoxy)-C₁₋₆alkyl; or R^(2M) and R^(2N) optionally combine to forman oxo group; or any two of R^(2M) and R^(2N) attached to adjacentcarbon atoms of the piperazine ring defined by R² optionally combine toform a fused ring selected from the group consisting of phenyl, C₂₋₅heteroaryl, C₄₋₈ cycloalkyl, and C₂₋₅ heterocyclyl, wherein each of thefused rings is optionally substituted one or more times by substituentsselected independently from R^(1Z); R^(1Z) is a halogen atom, oxo, —CN,nitro, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂,—O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C(O)—(C₁₋₆alkyl),—O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),—C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),—O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),—S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₃₋₁₀cycloalkyl, C₂₋₁₄heterocyclyl, C₆₋₁₄ aryl, C₂₋₁₄ heteroaryl, C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, C₂₋₆haloalkenyloxy,(C₁₋₆alkoxy)-C₁₋₆alkyl, C₁₋₆alkyl, or C₂₋₆alkenyl; R^(2G) is a hydrogenatom, C₁₋₆alkyl, C₁₋₆haloalkyl, or (C₁₋₆alkoxy)-C₁₋₆alkyl; R^(2L) is—C(O)—R³ or —C(O)—X¹⁴—R⁴; X¹⁴ is C₁₋₈alkylene, which is optionallysubstituted by one or more times by substituents selected independentlyfrom R^(1Y); R³ is a hydrogen atom, —OH, —NH₂, —O—R^(3B), —NH—R^(3B),—N(R^(3B))(R^(3C)), —O—C(O)—R^(3B), —NH—C(O)—R^(3B),—N(R^(3C))—C(O)—R^(3B), C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄aryl, or C₂₋₁₄ heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl,and heteroaryl are each optionally substituted one or more times bysubstituents selected independently from R^(3A), wherein any two R^(3A)attached to adjacent carbon atoms of the carbocyclyl, heterocyclyl,aryl, and heteroaryl groups to which they are attached optionallycombine to form a fused ring selected from the group consisting ofphenyl, C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, and C₂₋₅ heterocyclyl, whereineach of the fused rings is optionally substituted one or more times bysubstituents selected independently from R^(1Z), and wherein, whenR^(3B) and R^(3C) are attached to the same nitrogen atom, R^(3B) andR^(3C) optionally combine with the nitrogen atom to which they areattached to form a nitrogen-containing C₂₋₆ heterocyclic ring, which isoptionally substituted by C₁₋₄ alkyl; R^(3A) is a halogen atom, —CN,nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂,—O—R^(3D), —NH—R^(3D), —N(R^(3D))(R^(3E)), —C(O)—R^(3D), —O—C(O)—R^(3D),—NH—C(O)—R^(3D), —C(O)—O—R^(3D), —C(O)—NH—R^(3D),—C(O)—N(R^(3D))(R^(3E)), —S(O)₂—R^(3D), —O—S(O)₂—R^(3D),—NH—S(O)₂—R^(3D), —S(O)₂—O—R^(3D), —S(O)₂—NH—R^(3D),—S(O)₂—N(R^(3D))(R^(3E)), C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀ carbocyclyl,C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the alkyland alkenyl are each optionally substituted one or more times bysubstituents selected independently from R^(3Y), and wherein thecarbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionallysubstituted one or more times by substituents selected independentlyfrom R^(3Z); R^(3B), R^(3C), R^(3D), and R^(3E) are each independentlyC₁₋₈alkyl, C₂₋₈ alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄aryl, or C₂₋₁₄ heteroaryl, wherein the alkyl and alkenyl are eachoptionally substituted one or more times by substituents selectedindependently from R^(3Y), and wherein the carbocyclyl, heterocyclyl,aryl, and heteroaryl are each optionally substituted one or more timesby substituents selected independently from R^(3Z); R^(3Y) is a halogenatom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H,—C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),—C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),—O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),—S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,—O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl,C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the cycloalkyl, heterocyclyl,aryl, and heteroaryl groups are each optionally substituted one or moretimes by substituents selected independently from R^(1Z); R^(3Z) is ahalogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH,—NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),—C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),—O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),—S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, C₂₋₆haloalkenyloxy,(C₁₋₆alkoxy)-C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl,or C₂₋₁₄ heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, andheteroaryl groups are each optionally substituted one or more times bysubstituents selected independently from R^(1Z); R⁴ is a hydrogen atom,a halogen atom, —CN, nitro, oxo, —OH, —NH₂, —O—R^(4B), —NH—R^(4B),—N(R^(4B))(R^(4C)), C(O)—R^(4B), —O—C(O)—R^(4B), —NH—C(O)—R^(4B),—N(R^(4C))—C(O)—R^(4B), —C(O)—O—R^(4B), —C(O)—NH—R^(4B),—C(O)N(R^(4B))(R^(4C)), —S(O)₂—R^(4D), —O—S(O)₂—R^(4D),—NH—S(O)₂—R^(4D), —S(O)₂—O—R_(4D), —S(O)₂—NH—^(4D),—S(O)₂—N(R^(4D))(R^(4E)), C₃₋₁₀ carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄aryl, or C₂₋₁₄ heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl,and heteroaryl are each optionally substituted one or more times bysubstituents selected independently from R^(4A), wherein any two R^(4A)attached to adjacent carbon atoms of the carbocyclyl, heterocyclyl,aryl, and heteroaryl groups to which they are attached optionallycombine to form a fused ring selected from the group consisting ofphenyl, C₂₋₅ heteroaryl, C₄₋₈cycloalkyl, or C₂₋₅ heterocyclyl, whereineach of the fused rings is optionally substituted one or more times bysubstituents selected independently from R^(1Z), and wherein, whenR^(4B) and R^(4C) are attached to the same nitrogen atom, R^(4B) andR^(4C) optionally combine with the nitrogen atom to which they areattached to form a nitrogen-containing C₂₋₆ heterocyclic ring, which isoptionally substituted by C₁₋₄ alkyl; R^(4A) is a halogen atom, —CN,nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂,—O—R^(4D), —NH—R^(4D), —N(R^(4D))(R^(4E)), —C(O)—R^(4D), —O—C(O)—R^(4D),—NH—C(O)—R^(4D), —N(R^(4E))—C(O)—R^(4D), —C(O)—O—R^(4D),—C(O)—NH—R^(4D), —C(O)—N(R^(4D))(R^(4E)), C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₁₀carbocyclyl, C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl,wherein the alkyl and alkenyl are each optionally substituted one ormore times by substituents selected independently from R^(4Y), andwherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are eachoptionally substituted one or more times by substituents selectedindependently from R^(4Z); R^(4B), R^(4C), R^(4D), and R^(4E) are eachindependently C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₁₀ carbocyclyl, C₂₋₁₄heterocyclyl, C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the alkyl andalkenyl are each optionally substituted one or more times bysubstituents selected independently from R″, and wherein thecarbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionallysubstituted one or more times by substituents selected independentlyfrom R^(4Z); R^(4Y) is a halogen atom, —CN, nitro, oxo, —OH, —NH₂,—C(O)H, —O—C(O)H, —C(O)—OH, —NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl),—NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl),—NH—C(O)—(C₁₋₆alkyl), —N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl),—C(O)—O—(C₁₋₆alkyl), —C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂,—S(O)₂—(C₁₋₆alkyl), —O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl),—S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂,—O—(C₁₋₆alkylene)-O—(C₁₋₆alkyl), C₃₋₁₀ cycloalkyl, C₂₋₁₄ heterocyclyl,C₆₋₁₄ aryl, or C₂₋₁₄ heteroaryl, wherein the cycloalkyl, heterocyclyl,aryl, and heteroaryl groups are each optionally substituted one or moretimes by substituents selected independently from R^(1Z); R^(4Z) is ahalogen atom, —CN, nitro, oxo, —OH, —NH₂, —C(O)H, —O—C(O)H, —C(O)—OH,—NH—C(O)H, —C(O)—NH₂, —O—(C₁₋₆alkyl), —NH—(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C(O)—(C₁₋₆alkyl), —O—C(O)—(C₁₋₆alkyl), —NH—C(O)—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-C(O)—(C₁₋₆alkyl), —C(O)—O—(C₁₋₆alkyl),—C(O)—NH—(C₁₋₆alkyl), —C(O)—N(C₁₋₆alkyl)₂, —S(O)₂—(C₁₋₆alkyl),—O—S(O)₂—(C₁₋₆alkyl), —NH—S(O)₂—(C₁₋₆alkyl),—N(C₁₋₆alkyl)-S(O)₂—(C₁₋₆alkyl), —S(O)₂—O—(C₁₋₆alkyl), —S(O)₂—NH—(C₁₋₆alkyl), —S(O)₂—N(C₁₋₆alkyl)₂, (C₁₋₆alkoxy)-C₁₋₆ alkyl, C₃₋₁₀cycloalkyl,C₂₋₁₄ heterocyclyl, C₆₋₁₄ aryl, C₂₋₁₄ heteroaryl, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl, C₁₋₆haloalkoxy, orC₂₋₆haloalkenyloxy, wherein the cycloalkyl, heterocyclyl, aryl, andheteroaryl groups are each optionally substituted one or more times bysubstituents selected independently from R^(1Z); and n is 0, 1, or
 2. 2.The compound of claim 1, wherein X³ is >CH₂.
 3. The compound of claim 1,wherein n is
 0. 4. The compound of claim 1, wherein R^(1A) is methyl orethyl.
 5. The compound of claim 1, wherein R^(2G) is a hydrogen atom,methyl, or ethyl.
 6. The compound of claim 1, wherein X⁶ is —CH₂—,—CH₂CH₂—, —CH(CH₃)—, or —C(CH₃)₂—.
 7. The compound of claim 1, whereinX⁸, X⁹, X¹⁰, and X¹¹ are each >CH₂.
 8. A comestible or pharmaceuticalcomposition comprising a compound of claim
 1. 9. A method of reducingbitter taste of the composition, the method comprising introducing to acomposition a compound of claim
 1. 10. The method of claim 9, whereinthe composition is a comestible composition, which comprises one or morebitter compounds.
 11. The method of claim 10, wherein the bittercompounds are selected from the group consisting of: caffeine, quinine,tannins, catechins, polyphenols, menthol, potassium chloride, proteins,plant extracts, low-calorie sweeteners, and combinations thereof. 12.The method of claim 9, wherein the composition is a pharmaceuticalcomposition, which comprises an active pharmaceutical ingredient.